CHAPTER

Epilepsy
Michael A. Rogawski

1. lntraduction
Epilepsy, a condition of recurrent, paroxysmal seizures, is a
major, worldwide, health problem. The epileptic seizure represents
an abnormal synchronized discharge among a large population of
central neurons. Although the cause of this synchronized activity is
largely a mystery, the occurrence of seizures in an epileptic patient
can be diminished or eliminated by drugs that target the basic excit-
ability mechanisms of neurons. Most presently used antiepileptic
medications were deveIoped by empirical drug screening or seren-
dipity. However, in the past several decades, as understanding offhe
functional activity of brain circuits has increased, there has been an
intense effortto develop new antiepileptic medications on a rational
basis. Although progress has been measured, some rationally devel-
oped antiepileptic drugs are now entering the market.
The focus of attention for the rational design of antiepileptic
drugs has been to target, either directly or indirectly, ion-conducting
channels--the fundamental mediators of electrical excitability in
neurons. There are two major classes of neuronal ion channels: volt-
age-dependent channels that shape the subthreshold electrical
behavior of the neuron, allow it to fire action potentials, and regulate

Neurotherapeutics: Emerging Strategies

Eds.: L. Pullan and 4. Patel Hurnana Press Inc., Totowa, NJ
194 Xoga wski

its responsiveness EO synaptic signals; and neurotransmitter-rep-

lated channels that mediate the synaptic signals, Each of these two
classes of channel participates in the electrical events o f the seizure.
Voltage-dependent channels contributeto the paroxysmal depolariz-
ing shift, the single ceII correlate of the interictal (between seizure)
network discharge. Voltage-dependent channels also mediate action
potentials that allow transmission of the seizure discharge along
axons to neighboring cells and distant brain sites. The neurotransmit-
ter-regulated channels allow the abnormal discharge to propagate
between neurons within the neuronal aggregate and also participate
in the paroxysmal depolalizing shift. The voltage-dependent ion
channels include channels selective for Na+ and K+, that shape the
subthreshold behavior of neurons and mediate action potentials as
well as channels selective fox Ca2+that appear to play a critical, role
in absence seizures (see Section 7.). Neurotransmitterreceptor chan-
nels include the fast-acting channels for the major excitatory and
inhibitory neurotransmitters, glutamate and GABA, as well as far
regionally specific transmitters such as monoamines (catechola-
mines, serotonin, and histamine) and neuropeptides. In addition to
rapid actions, the transmitterscanmediate slower 'modulatory" sig-
nals, where the receptor is coupled to an ion channel via G-proteins
or other second messengers.
In principle, it may be possible to prevent the occurrence of
seizures by targeting any one or a combination of these systems, so
that there is an enormous variety of possible anticonvulsant strate-
gies. The ultimate goal is, of course, to prevent the generation or
propagation of seizure discharges without interfering with the nor-
mal functioning of the nervous system. (An additional and perhaps
more satisfying goal is to prevent the development of epilepsy; there
are some important leads along these lints as discussed in Section
3.1 .)Given the critical role of the neuronal excitability mechanisms
mediating seizures for normal brain function, it would seem improb-
able that an anticonvulsantdrugcould be developed which suppressed
seizures without producing side effects. Nevertheless, several pres-
ently available anticonvulsant drugs approach this goaI, indicating
that it is attainable.
 In this chapter, I consider a variety of approaches that are cur-
rently under investigation for the rational development of new anti-
epileptic drugs. The mechanisms of presently available antiepileptic
drugs has been reviewed previously (Rogawski and Porter, 1990),
and are not considered in detail here.

2. Potentiation of Synaptic Inhibition

Enhancement of synaptic inhibition mediated by GABAA
receptors is an important anticonvulsant strategy. This can occur by
targeting of the GABAA receptor itself, or by enhancement of synap-
tic GABA levels. Drugs that enhance GABAA receptor-mediated
inhibition show a distinctive spectrum o f activity in animal seizure
models. Such drugs typically protect very effectively against
pentylenetetrazol seizures, but have far weaker activity in the maxi-
mal electroshock test. Despite the selectivity of their effects in animal
seizure models, GAB&-receptor potentiating anticonvulsants may
have a broad spectrum of activity in human seizure disorders.
However, they are generally ineffective in absence seizures. (Benzo-
diazepine receptor agonists that do have anti-absence activity are a
notable exception to this rule.)
2.1. GABA, Receptors as Targets for Anh'epilep tic Drugs
Presently available drugs that potentiate GABAAreceptor
responses fa11 into two broad classes: benzodiazepine-like and bar-
biturate-like modulators. In addition, there are a variety of agents,
including neuroactive steroids and loreclezole, that act similarly to
barbiturates, but probably interact with distinct sites on the GABAA
receptor complex.
2.1.1. Novel Benzodiazepine Receptor Ligands
Benzodiazepine receptor agonists, such as diazepam and
lorazepam, have powerful anticonwlsant properties as a result of
their ability to enhance GABA A receptor-mediated neurotransmis-
sion in the central nervous system (CNS). Although such benzodiaz-
epine agonists have an impor.tant role in the acute treatment of status
epiiepticus (continuous seizures without return to consciousness),
196 Rogawski

two significant limitations largely preclude their chronic use in epi-

Iepsy therapy. The first limiting factor is that these benzodiazepines
produce undesirable side effects, including sedation and muscle
relaxation, at doses comparable to those that protect against seizures.
The second, and probably more important,Iirnitation is that tolerance
develops to the anticonvulsant activity of benzodiazepines receptor
agonists with chronic use. In recent years, considerable effort has
been directed toward developing strategies for overcoming these
limitations. A variety of benzodiazepines and nonbenzodiazepines
have been identified that interact with the benzadiazepine binding
site of the GABAn receptor complex in novel and potentially more
favorable ways. As yet, however, there is no convincing evidence
that any of these benzodiazepine receptor ligands will have practical.
utility in the chronic treatment of epilepsy.
2.1.1.1. RENZODIAZEPINE RECEPTORPARTIAL AGONISTS. Partial
aganisrn at the benzodiazepine receptorhasbeen proposed by Haefely
(see Haefely et al., 1990) as a promising approach to overcame the
undesirable side effects and the propensity to the development of
tolerance of full benzodiazepine agonists. Bartiat agonists have low
intsinsic efficacy and induce smaller responses than do full agonists
at the same fractional receptor occupancy. Thus, at full receptor
occupancy, partial agonists produce submaximal biological
responses.However, the degree of partial agonismmay vary depending
on the subunit composition of the GAB& receptor W f l a c h et al.,
1993). At anticonvulsantdoses, partial benzodiazepine receptor aga-
nists may produce less sedation and muscle relaxation than full ago-
nists, and may also exhibit less tolerance and physical dependence.
Benzodiazepine receptor partial agonists have been identified
within several structural classes, including me benzodiazepines
(bretazenil, FG 8205; Martin et al., 1988; Tricklebank et al., 1990),
P-carbolines (abecarnil, ZK 41296;Stephens et al., 1990;Petersen
et al., 1984), pyrozoloquinolines (CGS 9896; Bernard et al., 19851,
imidazopyrimidines (divaplon; Garher, 1988), and quinolizinones
(Ro 19-8022;Jencket al., 1992).Same partial agonist-for example,
Ro 19-8022-have anticonvulsant potency and efficacy in animal
seizure models comparable to full benzodiazepine receptor agonists
Epilepsy 197

(Jenck et al., 1992; Facklam et a]., 1992a; Jensen et al., 1 984). How-
ever, Ro 19-8022 has lower eficacy for sedation and muscle relax-
ation, and may also have reduced physical dependence liability.
Moreover, Ro 19-8022 does not exhibit proconvulsant activity (like
benzodiazepine inverse agonists); nor is an abstinence syndrome
(characterized by tremors and seizures) precipitated when chroni-
cally treated animals are exposed to a benzodiazepine receptor
antagonist. Interestingly, in line with the efficacy of conventionaI
benzodiazepines in human absence epilepsy, Ro 19-8022 has been
reported to be effective in a rodent genetic model of absence epi-
lepsy. Other benzodiazepine receptor partial agonists, including
bretazenil (Haigh and Feely, 1988; Facklam et aI., 1992a) and
divaplon (Feely et al., 1989; Deacon et al., 1991) similarly display
potent anticonvulsant activity, but less sedation and anticonvulsant
tolerance than diazepam. Studies using recombinant GABAn recep-
tor subunits have demonstrated that bretazenil and divaplon possess
35-58% and 2 1-28%, respectively, of the intrinsic efficacy of the
full agonist flunitrazepam (Knoflach et al., 1993; see also Facklam
et al., 1992b).
How can we understand the law propensity of benzodiazepine
receptor partial agonists to produce sedation, muscle relaxation, and
tolerance? It is now recognized that full benzodiazepine receptor
agonists, such as df azepam, produce anticonvulsant effects with low
receptor occupancy (Fig. I). For example, it has been estimated that
full benzodiazepine receptor agonists protect against sound-induced
seizures in mice at occupancy levels of 2-5% and against penty-
lenetetrazol seizures at occupancy levels of 25% (Braestrzlp and
Nielsen, 1986). In contrast, 70-90% occupancy is needed for protec-
tion against tonic hindlimb extension in the maximal electroshock
test (Petersen et al., 1986). Similarly, sedative effects as assessed
with various tests of motor impairment also require high levels of
occupancy (50-76%; Petersen et al., 1986). Thus, full benzodiaz-
epine receptor agonists exhibit anticonvulsant activity (against
sound-induced and pentylenetetrazol seizures) at low doses, and
sedation at higher doses. For partial agonists to elicit the same
response as a full agonist, higher levels of receptor occupancy are
 Xogawski

-
SPONTANEOUS
ABSENCE IRAT)
AUDIOGENIC

Fig. 1. The various actions of the full benzodiazepine receptor agonist

diazepam occur at different levels of receptor occupancy. Thus, partial ago-
nists may not produce behavioral effects requiring high IeveIs of occupancy,
such as impairment of motor function in the rotarod test. In vivo radioligand
method for determination of receptor occupancy is described in Petersen et al.
(1984). Audiogenic = protection against sound-induced seizures in DBN2
mice; MES =maximal electroshock test; DMCM =protection against seizures
induced by the benzodiazepine receptor inverse agonist merhyl 6,7-
dimethoxy-4-ethyl-b-carboiine-3-carboxylate.Data obtained in the mouse
(except as notedlare fromBraestmpand Nielsen (1 986), Petersen et al. (1984),
Jensen et al. ( 19X4),and Petersen et al. (1 986).

required, The requirement for higher occupancy is presumably

because the potentiation of each GABAAreceptor is smaller and
more GABAAreceptors must be recruited to obtain an equivalent
response. For example, in one study, 50% protection in the penty-
lenetetrazol test was reported to occur with 37% receptor occupancy
by diazepam and 84% receptor occupancy by ZK 91296, a partial
agonist (Petersen et al., 1986). For benzodiazepine agonist effects
that require a high degree of GABAAreceptor potentiation (e.g.,
 muscle relaxation, ataxia, amnesia, and respiratory depression), it
may not be possible to achieve the pharmacological effect with a
partial agonist, even with full occupancy. Thus, partial agonists can
have anticonvulsant activity and yet not show adverse side effects at:
any dose. There is substantial evidence that benzodiazepine receptor
tolerance occurs as a result of a downregulation in the expression of
certain GABAA receptor subunits, particularly the p subunit that
confers benzodiazepine sensitivity (Zhao et a1., 1994).Nevertheless,
since the mechanism coupling chronic receptor activation to changes
in the expressfan of the y2 subunit gene is not well understood, it is
not yet possible to explain the reduced tendency ofpartial agonists to
induce tolerance. Despite the very favorable properties af benzodi-
azepine receptor partial agonists, as yet there is no clinical data sup-
porting the utility of these compounds in epilepsy therapy.
Certain benzodiasepine receptor partial agonists, such as
abecamil, may have a distinct spectrum of anticonvulsant activity in
comparison with conventional benzodiazepine receptor agonists such
as diazepam (Turski et al., 1990). For example, abecarnil is highly
active in a variety of chernoconvulsant models (Sersa et al., 19921,
but, unlike diazepam, is inactive in the maximal electroshock test.
The differences in the spectrum of anticonvuEsant activity may relate
to the unique GABAA receptor subunit specificity of abecarnil.
Recent studies with cloned GABAA receptor subunits indicate that
abecarnil can exhibit partial or fuI1 agonist properties at different
GABAAreceptor subtypes, mainly dependent on the molecular form
of the a-subunit (Knoflach et al., 1993; PribiIla et al., 1993). Thus,
the unique phmacalogical profile of abecarnil could arise fromits
actions as a partial agonist at some GABAA receptors and as a fu11
agonist at others. Animals treated chronically with abe~arnildo not
exhibit a diazepam-like withdrawal syndrome on discontinuation of
the drug (Losches et al., 1990; Steppuhn et al., 1993; Llischer, 1993)-
Moreover, the development of anticonvulsant tolerance to abecarnil
is dependent on the model used. Indeed, in some experimental para-
digms no anticonvulsant tolerance is exhibited at the same time that
to1erance develops to the motor impairing activity of the dmg (Loscher
et al., 1991b; Serra et aI., 1994).
200 Roga wski

2.1.1 -2.BENZODIAZEPTNE RECEPTOR SUBTYPE-SELECTWE AGONTSTS.

Abecamil is an exampIe of a benzodiazepine receptor ligand that acts
as a partial agonist at some GABAA receptor subunit combinations
and not others. It therefore exhibits some subtype selectivity. The
imidazopyridines alpidem and zolpidem, in contrast, show nearIy
complete subtype selectivity. These compounds exhibit GABA
potentiating activity at, for example, GABAAreceptors of composi-
tion alBzyz,a2Ply2,alPlyz,but not aSP2y2(Faun-Halley et al., 1993;
Wafford et al., 1993; Horne et al., 1992). In binding to brain tissue,
alpidernand zolpidem show selectivity for the oli'BZ1 subtype ofrecep
tor (Benavides et al., 1988; Benavides et al., 1993).AIpidem has anti-
convulsant activity comparnbIe to benzodiazepines, but exhibits
much-reduced sedative and muscle relaxant activity (Garreau et al.,
1992). In addition, the drug fails to induce tolerance or dependence
(Perrault et al., 1993). Human trials of alpidem as an anxiolytic have
been promising, with a very favorable side-effect profile in compari-
son with conventional benzodiazepines.Alpidem binding exhibits a
differential regional: localization in brain that correlates roughly with
the presence of al/BZt binding sites. It has been suggested that the
regional selectivityofalpidemfor w t/BZl binding sites,which isdepen-
dent on the unique subunit specificity of the drug, could account for
its favorable properties (Benavides et al., 1993). On the other hand,
the possibility that alpidern is a partial agonist at certain GABAP,
receptor subtypes could also explain its favorable profile (Perrault et
al., 19933. However, recent studies with cloned subunits have dem-
onstrated that alpidern (Im et al., 1993) and zolpidem (Horne et al.,
1992) ase full agonists at some, if not aII, GABAAreceptor subtypes.
2.1.2. Barbifurafe-LikeDrugs
Barbiturates have fallen out of favor as anticonvulsant agents
largely because of their propensity to cause sedation, behavioral
impairment, and deleterious effects on cognitive performance
(Fawell et al., 1990).Nevertheless, barbituratesare highly effective,
broad-spectrum anticonvulsants. Barbiturate-like compounds with
improved side-effect profiles would provide interesting candidates
for clinical development.
Epilepsy 201

The sedative and anticonvulsant activity of barbiturates is

believed to be mainly due to their potentiationofCNS GABA-mediated
inhibition (Scholfield, 1938). This occurs by prolongation of burst
openings of single GABARreceptorchannels (Macdonaldet al., 1989).
However, effects on voltage-activated CaZ+channels also appear to
play a role in the sedative-hypnotic activity of the barbiturates and
could participate in their therapeutic activity as anticonvulsants
(ffrench-Mullen et al., 1993). In addition, direct activation o f the
GABAn receptor could account for the sedative-hypnotic side effects
of certain barbiturates (Rho et al., 1994b). Finally, barbiturates
appear to have actions an excitatory amino acid receptors, with
particular selectivity for AMPA (a-amino-3-hydroxy -5-methy 1-4-
isoxazalepmpionic acid) receptors (Taverna et al., 1994;Donevan and
Rogawski, unpublished). In line with the diversity of barbiturate cel-
lular actions, there are wide differences in the pharmacological prop-
erties of structurally similar barbiturates. Pentobarbital is a powerful
sedative-anesthetic, whereas the less sedative phenobarbital is used
mainly as an anticonvulsant. Although still incompletely understood,
the basis for the reduced sedation with phenobarbital may relate to
relative affinities for different target sites and also to the magnitudes
of effects produced at clinically relevant concentrations. For example,
it has been proposed that the strongly depressant action ofpentobarbita1
could relate to its activity both as a GABA potentiator and a Ca2+
channel blocker. Phenobarbital, in contrast, has a higher affinity for
GABAA receptors than for Ca2+channels (ffrench-Mullen et aI., 1993).
At clinically relevant concentrations, it may mainly act as a GABA
potentiator, but the absolute magnitude of the potentiation may be
smaller than that produced by pentobarbital. The lack of effect on Ca2+
channels and the less robust potentiation could account for its lower
toxicity. As the concentration of phenobarbital moves into the
supratherapeutic (toxic) range, it becomes more strongly sedative,
possibly because effects on Ca2' channels become prominent. The
types of Ca2+channels relevant to the action of barbiturates have not
been well defined. One hypothesis is that these are presynaptic chan-
nels involved in the regulation ofneurotransmitter release, and that the
depressant action is Iargely due to a reduction of glutamate release.
2 02 Roga wski

It may be possible to obtain even greater reductions in the seda-

tive-hypnotic activity of barbiturate-like GABA modulators. Thus,
the newly introduced anticonvulsant felbamate has a very favorable
side effect profile (causing agitation and insomnia more frequently
than sedation; Faught et al., 19931, and appears to act, in part, as a
barbiturate-like modulator of GABAAreceptors (Rho et aE., 1994~).
(Felbarnate produces certain severe idiosyncratic toxicities, unre-
lated to its anticonwlsant action, that limit its clinical utility.)
Felbamate is a dicarbamate structuralIy related to the sedative-
anxiolytic meprobamate. Meprobamate has also recently been shown
to have barbiturate-like activity. However, it is much more potent
and, unlike felbamate, can directly stimulate the opening of GABAA
receptor coupled CI-channels in the absence sf GABA (Rho et al.,
1994a). This latter activity could contribute to the propensity of
meprobamate to cause greater CNS depression. In addition to its
activity as a barbiturate-Iike modulator of GABAA receptors,
felbamate also can inhibit NMDA receptors as discussed in Section
3.1.5. This effect could produce behavioral activation that would
counterbalance the CNS depression resulting from GABA potentia-
tion. (NMDA antagonists typically have behavioral activating effects
at low doses; Willetts et al., 1990.)

It has been known for over five decades that the steroids proges-
terone and deoxycorticosterone acetate have anticonvulsant activity
against pentylenetetrazol seizures (Selye, 1942; Craig, 1966), In the
intervening years, other structurally related steroids, including 3,20-
pregnenedionesand 3,20-pregnanediones (Craig and Deason, J 968),
2P-morpholino-5a,3a-pregnanoIones(Hewett et al., 19641, and the
steroid anesthetic alphaxalone (Peterson, 1989), have been reported
to have similar activity. In 1984, Harrison and Simmonds made the
seminal discovery that alphaxalone could selectivelypotentiate cen-
tral neuron responses to GABA (but not glycine). The 3P-hydroxy
isomer betaxalone was inactive, indicating a high degree of structural
specificity. Morerecently, it has been recognized that certain endoge-
nous metabolites of progesterone and deoxycorticosterone are also
Epilepsy 203

highly potent modulators of the GABAn receptor (Majewska et aE.,

1986). These metabolites have anticonvulsant activity (Belelli et al.,
1989, 1990; Bogskilde et al., 1988), and their anticonvulsantpoten-
cies correlate strongly with their ability to modulate GABAAreceptor
current (Kokate et al., 1994). Studies using fluctuation (noise) analy-
sis and single channel recording have demonstrated that the steroids
produce a barbiturate-like prolongation ofburst openings of GABAA
receptors (Sirnmonds, 1991; Twyrnan and Macdonald, 1992). In addi-
tion, they may cause an increase in channel-openingfrequency, an effect
not observed with barbiturates. Like barbiturates, neuroactive steroids
can directly activate the GABAAreceptor in the absence of GABA.
Do neuroactive steroids have potential in the treatment of sei-
zure disorders? Although highly active against seizures induced by
pentylenetetrazol and other GABA receptor antagonists including
bjcuculline and picrotoxin, GABA-potentiating neuroactive steroids
are inactive in the maximal electroshock test. This contrasts with
phenobarbital which shows some activity in the maximal electroshock
test (Belelli et al., 1990).The profile of the steroids in animal seizure
models suggests that their primargr utility may be in the treatment of
absence epilepsy (Rogawski and Porter, 1990). Indeed, there is an
anecdotal report ofthe effectiveness of deoxycorticosterone acetate
in six of eight absence seizure patients (Aird and Gordan, 1951).
The extent to which neuroactive steroids can protect against
seizures at nontoxic (nonsedating) doses is not clear. All GABA-
potentiating neurosteroids cause impairment of motor performance.
However, there may be differences among stmcturally similar neu-
roactive steroids in relative toxicity. Progesterone and certain
pregnene and pregnane 3,20-diones exhibit a degree of separation
between their anticonvulsant and toxic doses, but are relatively weak
anticonvulsants(Craig and Deason, 1968). However, alphaxalone, a
mare potent anticonvulsant, protects against seizures only at doses
that produce neurological impairment (Peterson, 1989).In a compre-
hensive study of progesterone and deoxycorticosteronemetabolites,
there was up to a several-fold separation between the protective and
toxic doses. Thus the therapeutic index (ratio of the ED50 values for
motor impairment and for protection in the pentylenetetrazol seizure
test) ranged from 1.2-3.8 (Kokate et al., 1994). However, the thera-
peutic indices of a11 of the steroids were less than that of the benzo-
diazepine clonazepam (8.9). Recently, steroid-like substituted
bentejindenes (tricyclic molecules containing only a portion of the
steroid A-ring) have been described which potentiate GABA
responses and may have toxicity comparable to the most favorable
neurosteroids (Rodgers-Neame et a1., 1992). Further structure-
activity studies may lead to the identification of steroids with
improved toxicity profiles. However, a key-but as yet unan-
swered-question is whether neurosteroids will exhibit tolerance as
do benzodiazepines. If so, like benzodiazepines, they will have lim-
ited utility in the chronic therapy of seizure. (A recent study failed to
observe any tolerance to the anticonvulsantactivity ofpregnanolone
in the pentylenetetrazol test; Kokate et aI., 19956.) However, even if
tolerance does develop over time, steroids may stiIl be of value in the
acute treatment of status epilepticus, as are benzodiazepines. In fact,
the steroids appear to be highIy effective in the kainate and piIo-
carpine models ofstatusepilepticusin the mouse (Kokate andRogawski,
1994; Kokate et al., 1995a). Because the solubility of steroids is poor,
selection of an appropriate vehicle or identificationo f water soluble
prodrug forms will be critical.
Recently, the synthetic 3P-methyl analog of epiallopregnano-
Ione (3a-hydroxy,3P-methyl-5a-pregnan-20-one; CCD 1042)has
been demonstrated to have anticonvulsant potency that is only
slightly weaker than its parent. However, the 3P-methylation confers
good metabolic stability and oral activity. In Phase I cIinical trials,
CCD 1 042was well-toleratedat levels substantially higher than those
associated with seizure protection in animals (K.W. Gee, personal
communication, 1995).
2.1.5. y-Bufyrolactones and y-Thiobutyrolactones
An additional series of GABAA receptor modulating compounds
has recently been described that appear to act at a site distinct f o m
benzodiazepines, barbiturates, and steroids (Holland er aI., 1993).
This novel recognition site, referred to as the y-butyrolactone (GBL)
site, is the locus of action of a variety of substituted y-butyolactones
Epilepsy 205

and y-thiobutyrolactones.Certain ligands ofthe GBL site antagonize

GABAAreceptorresponse and are convulsant, whereas otherspoten-
tiate GABA responses and have anticonvulsantproperties (Holland
et al., 1990). Anticonvulsant GBL site ligands, such as a-ethyl,a-
methyl-thiobutyrolactone (a-EMTBL), are protective in the penty-
lenetetrazol seizure model as are other GABA-potentiating drugs.
However, GBL site ligands may also be effective in the maximal
electroshock test and other seizure models (Ferrendelli et al., 1989;
Holland et al., 1992).a-EMTBL has a therapeutic index that is low
relative to other GABA modulating anticonvulsants, but i s similar to
valproate. Preliminary results indicate that a-EMTBL may demon-
strate less tolerance thanclanazepan, suggestingthat GBL site ligands
may be ofutiIity in chronic epiIepsytherapy (Ferrendelli et al., 1993).

Loreclezole is a novel triazole derivativethat is protective against

pentylenetetrazol seizuresbut is less active in the maximal electroshock
test (Wauquier et al., 1990; Kulak and Sobaniec, 1994). In addition, at
low, nontoxic doses, the drug has anti-absence activity in a genetic
model of generalized absence epilepsy (Ates et al., 1992). Conse-
quently, loreclezole has a profile of activity similar to that of other
benzodiazepines. A potential benzodiazepine-Iike interaction with
GABA, receptors is suggested by the observation that the anticon-
wlsant effects of loreclezole can be reversed by benzodiazepinerecep-
tor inverse agonists (Vaught and Wauquier, 199 1; Ashton et al., 1992).
The benmdiazepineantagonistflumazenil, however, failed to alterthe
anticonvulsantactivity of loreclezole,indicating that loreclezole is not
a benzodiazepine receptor agonist (Wauquier et al., 1990).Moreover, on
chronic (5-7 d) administration, tolerance did not develop to the anti-
conwlsant effects of Ioreclezole as it does with benzodiazepines.
LorecEezole can indeed enhance the activity of GABAArecep-
tors, but it interacts with a novel allosteric modulatory site distinct
from that of benzodiazepines, barbiturates, or neuroactive steroids
(Wafford et al., 1 994). Using native rat and cloned human GABAA
receptors, loreclezole strongly potentiated GABA-activated C1- cur-
rent. However, activity of the drug did not require the presence of the
y-subunit and was not blocked by flumazenil, confirming that
loreclezoIe does not interact with the benzodiazepine recognition
site. Interestingly, loreclezole had >300-fold activity an receptors
containing the PI- or p3-subunitin comparison with those containing
the I subunit. Using chimeric P-subunits and site-directed mutagen-
esis, it was demonstrated that a single amino acid, at the carboxyl-
terminal end of the P-subunit putative channel-lining domain TMZ,
confers sensitivity to loreclezole (Wingrove et al., 1994). The affin-
ity for GABA and benzodiazepines was unaltered by amino acid
substitutions at this site.
Loreclezole reduced seizuse occurrences in several small clini-
cal trials and was rdatively free sf side effects (Rentmeester and
Hulsman, 19921, demonstrating the potential of drugs that modulate
GABAAreceptors in novel ways.
2.2. Vigabatrr.'~~,
a GABA Transamitrase Inhibitor
In addition to the focus on postsynaptic GABAnreceptors, there
has been considerable interest and, indeed, success in the develop-
ment of new antiepileptic drugs that modify GABA disposition in the
brain. Vigabatrin (y-vinyl-GABA), perhaps the most notable achieve-
ment in this respect, is an enzyme-activatedirreversible inhibitor of
GABA transaminase, the main degradative e n m e for GABA. The
drug elevates brain GABA levels, and exhibits anticonvulsant activ-
ity in a variety of animal seizure models. Moreover, there is now
substantial clinical data supporting its efficacy in the treatment of
human seizure disorders (Reynolds, 1992).Although the precise way
in which vigabatrin prevents seizures remains unclear (Bernasconi et
al., 19881, GABA transaminase inhibition may increase neuronal
GABA in a releasable pool, so that larger amounts of GABA are
discharged with stimulation (Gale, 1992). Thus, increased amounts
of GABA are released in a use-dependem fashion, as needed, during
seizures, It had been believed that tolerance develops only to the
sedative side effects ofvigabatrin, but not to its anticonvulsantactiv-
ity (Remy and Beaumont, 1989). Now, however, there is emerging
evidence that tolerance may also developto the therapeutic effects of
the drug (Martin and Millac, 1993).
Epilepsy 207

2.3. GABA Uptake Blockers

An alternative approach to increasing synaptic GABA levels is
inhibition of GABA reuptake. A variety of cyclic amino acids,
includingnipecotic acidand guavacine, inhibit glial orneusonal GABA
uptake carriers. In general, however, thcse compounds have only
modest potency in vitro and do not enter into the CNS after parented
administration. In recent years, n variety of lipophilic analogs of
nipecotic acid and guavacine have been described (Braestrup et al.,
1990;Suzdak, 1993;Andersenet al., 1993).These compozand~which
include tiagabine, CI-966, NNC-7 11, and SKF lQ0330A---are highly
potent and specific inhibitors of GABA uptake into glia and neurons,
but have essentially no activity on other uptake transporters. Unlike
nipecotic acidwith its moderate selectivityfor neuronal GABAuptake,
lipophilic GABA uptake inhibitors such as tiagabine show a modestly
greater affinity for glial uptake, but they do inhibit uptake in both cell
types. These compounds are not transported via the GABA uptake
carrier nor do they stimulate GABA release. Recently, it has been
demonstrated that tiagabine, CI-966, and related lipophilic GABA
uptake inhibitors are highEy selective for the GAT-1 cIoned GABA
transporter, the predominant form in rat brain (Burden et al,, 1994).
Using in vivo microdialysis in rodents and primates, the systemic
administrationof CI-966 (Taylor et al., 1990)or tiagabine (Fink-Jensen
et al., 1992; Sybirska et al., 19933was shown to increase extracellular
GABA overflow. Similar results were obtained in awake human sub-
jects with hippocampal microdialysis probes foIlowing acute oral
administration of tiagabine (During eta]., 1992). Experiments in brain
slice preparations have demonstrated that Iipephilic GABA reuptake
blockers can prolong the action of applied GABA and aEso increase the
amplitude and duration of inhibitoy GABA-mediatedsynaptic poten-
tials (Reckling et aI., 1990; Thompson and Gahwiler, 1992). In addi-
tion, these compounds inhibit epileptiform activity in the slice.
Lipsphilic GABA uptake inhibitors have a spectrum s f anti-
convulsant activity in animal seizure models that is similar to other
drugs which act on brain GABA systems, such as the benzodiaz-
epines. These compounds are highly effective in protecting against
pentylenetetrazol seizures and may also have activity against sei-
 zures induced by other chemoconvulsants that interfere with GABA-
ergic neurotransrnission, such as the benzodiazepine receptorinverse
agonist DMCM (methyl 6,7-dimethoxy-4-ethyl-barboline-3-car-
boxylate). They are far less potent (tiagabine: Nielsen et al., 199 1) or
inactive (SW 89976A and SKF 100330-A: Swinyard et al., 1991) in
the maximal electroshock test. In addition, lipophilic GABA uptake
inhibitors have shown activity in various reflex seizure models
(including the photosensitive baboon Papio papio), and in the
amygdala and corneal kindIing models (Suzdak, 1993; Swinyard
et al., 1991; Smith et al., 1995). At doses higher than those required
to protect against seizures, lipophilic GABA uptake inhibitors pro-
duce neurological impairment, as do other drugs that enhance
GABAergic neurotransrnission.However, there is evidence that tol-
erance may develop to these side effects,but not to the anticonvulsant
activity (Suzdak, 1994). LipophiIic GABA uptake inhibitors have a
spectrum of anticonvulsant activity in animal seizure models that is
distinct from the important presently marketed antiepileptic drugs
(Swinyardet aE., 199 1). Therefore, it is difficultto predict fromanimal
studies which farms of human epilepsy would be most amenable
to therapy with these agents. However, their potency and rela-
tively broad spectrum of activity suggest that they are interesting
candidates for further development.
In human clinical trials, tiagabine has shown activity against
complex partial seizures, with an overall incidence of side effects no
different fiom placebo at therapeutic doses (Mengel, 1994). v o w -
ever, adverse side effect such as headache, tiredness, and dizziness
were obsmed with increased doses.) Importantly, there was no evi-
dence of tolerance to the drug's anticonwlsant activity with chronic
dosing for up to 12 mo.In contrast, in an initial trial in healthy voIun-
teers, CL-966induced a variety of severe neurological and psychiatric
symptoms (Sedman et al., 1990). There are differences between the
pharmacological properties oftiagabineand CI-966 that could account
for the striking differences in the clinical responses to the two drugs
(see Suzdak, 1993). AItematively, it may simply be that the initial
doses chosen for CI-966 were excessive. It is uncertain whether the
favorable safety record of tiagabine will be maintained in larger tri-
Epilepsy 209

als. The available infomation suggests that cautious optimism about

the potential of lipophilic GABA uptake inhibitors is warranted.
2.4. Potenfintion, of GABA Release
Although drugs that elevate synaptic GABA levels by interfer-
ing with GABA removal mechanisms have anticonvulsant activity,
the continuously elevated GABA levels may have untoward effects.
A theoretically more attractive approach would be to increase the
amount of GABA released with each synaptic stimulus. At present,
no selective GABA releasing agents have been described. However,
there is some preliminary evidencc that the clinically effective anti-
epileptic drug gabapentin could act by such a mechanism.
Although gabapentin was originally synthesized as a GABA
analog, it does not interact with GABAa or GABARreceptors, is not
metabolicalIy converted to GABA or a GABA receptor agonist, and
does not inhibit GABA uptake or degradation (Taylor, 1994).Haw-
ever, gabapentin does increase GABA turnover in some brain regions
(Loscher et al., 199 1a) and may increase the release of GABA from
brain slices in vitro (Gdtz et al., 1993).Recently, it has been observed
that gabapentin can potentiate electrophysiological responses to
released GABA in rat neonatal optic nerve, presumably by increas-
ing release from gIia (Kocsis and Homou, 1994). A similar effect
has been reported in the hippocampus (Honmou et aI., 1994).
Although these studies with gabapentin and GABA release are
intriguing, they are as yet inconclusive. Nevertheless, they serve to
focus attention on the possibility that drugs that enhance GABA
release could have potential as antiepileptic agents.
2.5. Potentiation of GABA and Glycine:
Propofol and Chlomethiazole
The anesthetic propofol(2,6-diisopropylphenol) is a structurally
novel barbiturate-like modulator of GABAn receptors (Peduto et aI.,
1991). However, in contrast to barbiturates such as pentobarbital, sev-
eral recent reports have suggested that subanesthetic doses ofpropofol:
can protect against seizuresin animal rnodeIs, with minimal behavioral
side effects (Hasanetal., 1992;al-Haderetal., 1992;Hasan and Wolley,
210 Roga wski

1 994). In humans, propofol may be effective in the treatment of status

epilepticus (Wood et al., 1988), although the drug has also been
reported to cause seizures under certain circumstances (Makela et a].,
1993). Propof01 produces an enhancement of GABA-activated C1-
current and, at high doses, can directly activate GABAA receptors
(Hales and Lambed, 199 1). In additionto these barbiturate-like prop-
erties, propofol is also able to potentiate glycinc-evoked currents
(Hales and Larnbert, 199 1 ;but see, Dolin et al., 1992), an action not
shared by barbiturates, neuroactive steroids, or benzodiazqines.
Another combined GABAA/glycinemodulator for which there
is even more clinical information is chlormethiazole, a thiamine
derivative with sedative, hypnotic, anxiolytic, and anticonvulsant
properties ( ~ g r e n 1986).
, ChlormethiazoIe is particularly effective
in the matment of status epilepticus (even in cases failing to respond
to benzodiazepines and barbiturates). Chlomethiazole is a1so used
inpreeclampsia(toxemia of pregnancy), eclampsia (toxemia of preg-
nancy with seizures), and the alcohol withdrawal syndrome. En both
animals and humans, chlormethinzoIe has anticonvulsant activity at
doses that do not produce sedation. Like propofol, chlormethiazole
potentiates responses to both GABA and glycine, and can also directly
activate GABAAreceptors (Wales and Larnbert, 1992). Propofol and
chlonnethiazole uniquely potentiate GABA and glycine, and both
appear to be effective anticonvuIsantswith low behavioral toxicity at
anticonwlsant doses. The favorable toxicity could be explained if
the potentiation of GABA and glycine were additive (or even syner-
gistic) for seizure protection, but were not additive for sedative side
effects. Indeed, it is not apparent that a glycine potentiating drug
would exhibit sedative-hypnotic activity.

3. Interactions with Excitatory

Amino Acid Receptor Systems
A complementaryapproach to facilitation of synaptic inhibition
is blockade of synaptic excitation. The bulk of fast synaptic excita-
tion in the CNS is mediated by the excitatory amino acid glutamate,
acting on AMPA (a-amino-3-hydroxy-5=methyl-4-i~0~au,lepropi0ni~
acid) and NMDA (N-methyl-D-aspartic acid) receptors. In recent
years, there has been intense interest in the medicinal chemistry of
excitatory amino acid antagonists because sf their potential in the
treatment of neurological disorders, including epilepsy. The con-
viction that excitatory amino acid antagonists have a roIe in epilepsy
therapy is based on extensive in vitro and in vivo evidence that
NMDA and AMPA receptors participate in the expression of many
types of epileptic seizures (Rogawski, 1995). Recently, it has been
elegantly shown using microdialysis that glutamate levels are
eIevated prior to the onset and during the expression of complex
partial seizures in human subjects (During and Spencer, 1993).There
is thus strong theoretical support for the potential utility of excitatory
amino acid antagonists in the treatment of human seizure disorders.
However, as yet, this has not been verified in clinical trials.
3.1. NMDA Receptor Antagonists
NMDA receptor antagonists have a broad spectrum of activity
in animal seizure models. NMDA antagonists are particularly potent
in the maximal electroshock test in rodents and against reflex sei-
zures in rodents and primates (Chapman and Meldrum, 1993). They
are also protective against pentylenetetrazol and other chemoconvul-
snnts. Thus, the resuIts from animal testing suggest that NMDA
antagonists may have utility in the treatment of generalized tonic-
clonic (convulsive) and partial seizures. NMDA antagonists have
lower potency against spontaneous absence-like seizures in rodents,
so that they are less likely to be of utility in human absence seizures.
A particularly interesting feature of NMDA antagonists is their pow-
erful ability to protect against the induction of kindled seizures in
vivo and against kindling-like phenomena in the in vitro hippocam-
pal ~Iicepreparation(see Rogawski, 1995). This suggests that NMDA
antagonists may prevent the development or progression of some
types of seizures. This property could be of value in certain cIinicaI
situations, such as during the critical period after brain injury or in
progressive childhood epilepsies. The status of efforts to develop a
safe and effective NMDA antagonist for use in epilepsy therapy has
been recentIy reviewed (Rogawski, 1992).
 3.1.1. Competitive NMDA Recognition Site Antagonists
In 1982, Croucher et al. reported that phosphonic acid competi-
tive NMDA recognition site antagonists were protective against
sound-inducedand minimal pentylenetetrazol seizures in mice. This
important observation stimulated an intensive research effort into the
medicinal chemistry of NMDA receptor antagonists (Rowley and
Leeson, 1992). Numerous structural classes of NMDA antagonists
have been investigated.Perhaps the most mature line of investigation
is that evolving from the straight chain o-phosphono-a-aminoacid
compounds that were the basis of the study by Crouchex et al. (see
Watkins, 1991). The original compounds are very polar and as a
consequence have poor brain penetration. However, cyclic analogs
with the amino nitrogen in a six-member ring, as in CGS 19755 (cis-
4-phosphonomethyl-2-piperidine carboxylate; Hutchison et al.,
1989; Lehrnann et al., 1988),or in a piperazine ring, as in CPP (3-[2-
caxboxypiperazin-4-yllpropyl-1-phosphonate; Davies et al., 1986;
Lehmann et al., 1987), had improved systemic activity, and were
even effective orally (Pate1 et al., 1990). It was subsequently found
that uunsaturation sf the chain, as in CGP 37849 ([El-2-amino-4-
methyl-5-phosphono-3-pentanoicacid; Fagg et al., 1990;Schmutz et
al., 1990; De Sarro and De Sam, 1992), or addition of a ketone as in
MDL 100453 ~[R]-4-oxo-5-phosphonowaline; Whitten et aE., 1990)
also resulted in compounds with powefil systemic anticsnvulsant
activity. Moreover, the carboxyethylester of CGP 37849 (CGP
3955 1) showed particularly prolonged oral anticonvulsant activity
(De Sarro and De Sarro, 1992). (The reduced analog MDL 10453
also is a potent NMDA antagonist;Bigge et al., 1992.) Unsaturation
of the side chain of CPP to form CPPene (Aebischer et al., 1989)
similarlyproduced an anticonvulsant compoundwith a long duration
of action, The D(-)-enantiorner is the active species of CPPene and
has been used in several studies. D(-)-CPPene has protective activity
in a variety of reflex epilepsy models (Patel et al., 1990; Smith and
Chapman, 1993; Smith et al., 1993; De Sarm and De Sarro, 1993)
and, as is the case for other NMDA antagonists, protects against the
development of kindled seizures (Durmurnuller et al., 1994). Most
competitive NMDA recognition site antagonists have a phosphonic
Epilepsy 223

acid group as in the original structures produced by Watkins (1 991).

However, this is not essential to activity as demonstrated by
LY233053 and LY275059, in which she phosphonic acid group is
replaced by the bioisosteric tetrazol functionality. LY233053 offers
good protection against NMDA and maximal electroshock seizures,
but its duration of action is short (Schoepp et al., 1990a,b; Ornstein
et al,, 1992). The structurally novel bicyclic phosphonic acid
LY2746 14 has long lasting oral anticonvulsant activity (Schoepp
et al., 19913, whereas the corresponding tetmzol LY233536 (Leander
and Ornstein, 1990; Omstein et al., 19901, like LY233053, has a
more sapid time course.
CompetitiveNMDA recognition site antagonistsexhibit a broad
spectrum of activity in animal seizure models. Not unexpectedly,
these compounds are highly effective in protecting against seizures
and lethality induced by systemic or intracerebroventricular NMDA.
They are also protective in the maxima1 electroshock test with corn-
parabIe or slightly lower potency (Ferkany et nl., 1989). Protection
is also conferred against pentylenetemzol-induced clonic seizures,
but typically at somewhat higher doses. However, a structurally
unique cyclic phosphonic acid NPC 12626(2-amino-4,5-[1,2-cyclo-
hexyll-7-phosphonoheptanoiGacid) has been described which is less
potent in the maximal electroshock test than against NMDA or penty-
lenetetrasol seizures (Ferkany et al., 1989). Recently, the highest
potency isomer of NPC 12626 has been identified as the ZR,4R,5S
form (Hamilton et al., 1993). It too shows a reverse ordering of
potencies in animal seizure models (Ferkany et al., E 993). Whether
this unique profile is related to an unusual selectivity for NMDA
receptor subtypes or some other property remains to be determined.
Although diverse NMDA recognition site antagonists with good
bioavailability and favorable pharmacokinetic properties are now at
hand, the problemof side effects has not been so readily solved. Since
NMDA receptors are critical to numerous brain functions, NMDA
antagonists can produce a variety of behavioral and neurological
toxicities. There are, however, certain encouraging features of the
preclinical profile of competitive NMDA recognition site antag-
onists. AnticonvuIsant effects typically occur at doses below those
 that produce motor impairment (De Sarro and De Sarro, 1993;
Ferkany et al., 1993). However, the separation between anti-
conwlsant activity and motor toxicity is typically smaller than for
other anticotkvulsantdrugs. Drug discriminationstudies indicate that
the subjective effects of competitive NMDA recognition site antago-
nists in rodents and primates are distinct from those of dissociative
anesthetic-like NMDA antagonists(Gold and Balster, 1993; Bobelis
and Ralster, 1993). While competitive antagonists do not seem to
have the same propensity for producing certain behavioral side
effects such as stereotypies and disturbances of locomotor behavior
common with dissociative anesthetic-like NMDA antagonists (see
Section 3.1.2.), these stiIl occur. The side effects may be especially
prominent in kindled animals (Loscher and H~nack,199 1a,b). Tol-
erance does not seem to develop to either the therapeutic activity or
the side effects (Smith and Chapman, 1993)-
Despite the various favorable properties ofNMDA recognition
site antagonists,reports of clinical trials have been disappointing. In
an open-Iabel study of D-CPPene in eight patients with intractable
complex partial seizures, a 1patients withdrew prematurely because
of side effects. The side effects included poor concentration, seda-
tion, ataxia, depression, dysarthrta (impairment of speech due to
motor impairment), and amnesia (Sveinbjornsdottir et al., 1993).
None of the patients experienced a reduction in seizure frequency.
Interestingly, healthy volunteers tolerated much higher doses than
the patients. Thus, as in kindled animals, patients with epilepsy may
have greater sensitivity to the side effects of NMDA antagonists. A
final problem is that competitive antagonists (like the dissociative
anesthetic-like compounds discussed in Section 3.1.2.) can produce
neuronal vacuolization and morphological damage in certain brain
regions (Olney et al., 1991).
Until recently, it was not appreciated that competitive N M 9 A
recognition site antagonists exhibit differing activities at NMDA
receptors composed of different subunit combinations. The informa-
tion now available indicates that this is the case. Thus, CPP appears
to have modestly higher affinity for NMDA receptors composed of
W D A R l - l b subunits that contain a 2 1 -amino acid insert generated
by alternative splicing of exon 5 (see McBain and Mayer, 1994). In
addition to sensitivity to competitive antagonists, this N-terminal
variation determines a variety of functional properties of the NMBA
receptor, including potentiation by ZnZ+and polyamines and inhibi-
tion by protons (HolImann et al., 1993). In the future, it may be
possible to more selectively target specific NMDA receptor subunit
combinations, thus potentially providing for the development o f less
toxic anticonvulsants.
3.1.2. Channel-BlockingNMDA Receptor Antagonists
The NMDA receptor channel blockers are often referred to as
'kncompetitive" antagonists, because their binding and blocking
action requires the receptor-channel to be gated in the open state.
Occupancy of a binding site within the ionophore of the NMDA
receptor prevents cation flux through the channel, thus producing a
functional block of NMDA receptor responses (MacDonald et al.,
199 1 ). Unlike competitive NMDA recognition site antagonists,
uncompetitive antagonists share with other noncompetitive antago-
nists of the NMDA receptorthe theoreticaI advantage that their block-
ing action wouldnot be overcome by high synaptic levels of gIutamate
asmay occur during seizures. In addition, uncompetitive antagonists
have the additional theoretical advantage of use-dependence, imply-
ing that their inhibitory action may specifically be potentiated at sites
of excessive receptor activation. The current status and potential
clinical utiIity of channel-blockingNMDAreceptor antagonistshave
recently been reviewed (Rogawski, 1992, 1993).
Channel-blocking NMDA receptor antagonists fa11 into two
broad categories:dissociativeanesthetic-like agents and Iow affinity
antagonists. Shortly after the discovery of selective competitive
NMDA recognition site antagonists in the early 1980s, the dissocia-
tive anesthetics phencyclidine and ketamine were demonstratedto be
effective NMDA receptor antagonists (Anis et al., 1983). The struc-
turally dissimilardissociativeanesthetic-likeagent dizocilpine (MK-
801) is also an extremely potent NMDA receptor antagonist. These
compounds exert their block in a use-dependentand voltage-depen-
dent fashion, indicating that they act by an open-channel mechanism
21 6 Roga wski

(Huettner and Bean, f 9881, Like competitive NMDA recognition

site antagonists, dissociative anesthetics are potent broad spectrum
anticonvulsants in a wide variety of animal seizure models (see
Rogawski, 1992). However, at anticonvulsant doses, they produce
severe neurobehavioral side effect-including cognitive, sensory,
and various schizophrenia-like deficits (Krystal et al., 1994)-that
limit their potential clinical utility. In addition, dissociative anes-
thetics have been reported to cause reversible vacuolization in rat
cortical neurons at low doses (Olney et al., 1989, 19911, and frank
necrosis at higher doses (Fix et al., 1993). The propensity of dissocia-
tive anesthetics to cause neuronal injury is shared by many NMDA
antagonists, raising doubts as to overall safety of such compounds.
However, caution must be exercised in extrapolating the histo-
pathdogical findings obtained in rats to other species. Indeed,
NMDA antagonist-induced pathomorphological changes have not
been documented in primates. Moreover, it is now apparent that
some NMDA antagonists may produce only transitory vacuoIization
with no necrosis, or no changes at all.
The anticonvuIsant activity of dissociative anesthetics is shared
by a variety of channel-blocking NMDA antagonists, some of which
are analogs of the dissociative anesthetics and others that are struc-
turally distinct. Certain of these compounds have substantially
reduced behavioral toxicity in animals. For several, there is human
clinical experience documenting an acceptable level of safety. These
reduced-toxicity channel-blocking NMDA antagonists have been
referred to as "low affinity" uncompetitive antagonists. However,
low affinityper-semay not be the only factor that accounts for their
more favorable toxicity characteristics (see below).
The existence of low-toxicity, channel-blocking NMDA antag-
onists was first recognized with the discovery that certain l-phenyl-
cycloalkylamines such as 1-phenylcyclahexylamine(the analog of
phencyclidine substituting a primary amine for the piperidine ring)
and 1-phenylcyclopentylaminewere effective anticonvulsants, but
had a reduced propensity to produce motor impairment at anticon-
vulsant doses (Rogawski et nl., 1988, 1989; Thurkauf et al., 1990;
Blake et nl., 1992). Later, an analog of dizocilpine ADCI (5-amino-
Epilepsy 217

carbonyl-l0,11-dihydro-5H-dibenzo[a,~cyclohepten-5,IO-imine)
was observed to have similar properties, and also to retard the devel-
opment of kindled seizures (Rogawski et al., 1991). These com-
pounds displace binding of dissociative anesthetic receptor Iigands
(pH]1 -[l-(2-thienyl)cyclohexyl]piperidine and [3H]dizocilpine) to
brain membranes and block NMDA receptor currents in a use-depen-
dent and voltage-dependent manner, indicating that they are chan-
nel-blocking NMDA antagonists (Rogawski et aI., 1992; Jones
and Rogawski, 1992). However, the binding affinities of these
reduced-toxicity uncompetitive NMDA receptor antagonists are lower
than that of phencyclidine and dizocilpine. At equieffective concen-
trations, these lower affinity ligands would exhibit faster apparent
rates of block and unblock, and this may,at least in part, account for
the lower toxicity (see Rogawski, 1993). However, reduced binding
affinity alone cannot completely explain the lower toxicity since
there is an imperfect correlation between binding affinity and thera-
peutic index (Rogawski et al., 1989). Moreover, ketamine, a drug
with strong dissociative anesthetic properties, has a binding affinity
comparable to many of the less toxic channel-blocking agents. In
fact, there is now evidence that lower toxicity Iigands may bind selec-
tively to a differentpopulation ofNMDAreceptors than do dissociative
anesthetics (Porter and Greenmyre, 1995).
Recent work with cloned NMDA receptor subunits suggests
that there may be differences among subunit combinations with
respect to their sensitivity to channel-blocking agents (McBain and
Mayex, 19943. For example, assembly of the NMDAR1 subunit with
NR2C generates receptors with lower affinity for some channel
blockers than is the case with NR2A orNR2B. In addition, the pres-
ence of exon 5 in NMDAR1 (the NMDARl- 1b splice variant; see
Section 3.1. 1.) confers higher sensitivity to block by dizocilpine and
ketarnine (Hollmann et al., 1993; Rodriguez-Paz et al., 1995). More
subtle variations in the structure of NMDA receptors could also
modify the actions of channel bIockers. A particularly critical site of
the NMDARl subunit is the neutral asparagine at position 598. This
correspondsto the edited arginineJgIutamine (QIR)site in membrane
segment 2 (M2) of AMPA receptors, where a positively charged
 arginineresidue in GluR2 confers low Ca2+pemeability(see Section
3.2.2.). Similarly, mutations in NMDAR1 that switch the asparagine
to a positively charged arginine generate receptors resistant to block
by dissociative anesthetics (Kawajiri and Dingledine, 1993; Mori
et al., 1992; Sakurda et a]., 1993). Although there is currently no
evidence for RNA editing of NMDA receptors at this site (as occurs
for AMPA receptor subunits), variations in channel structure in
this or a nearby region of the receptor could have important conse-
quences for the sensitivity to channel blockers. Of course, it remains
to be determined which, if any, structural variation in the NMDA
receptor accounts for the selective binding of low-affinity channel-
blocking NMDA antagonists, and, moreover, whether this contrib-
utes to their more favorable toxicity characteristics. Factors other
than binding affinity and subunit selectivity might also contribute to
the more favorable side-effect profiles ofcertain low-affinity NMDA
antagonists (Rogawski, 1993). In particular, synergism between
effectson NMDA receptors and other anticonvulsanttargets could be
a factor in some circumstances.For example, ADCI has Na* channel
blocking activity similarla carbamazepine (see Section 4.1, although
the extent to which this occurs at concentrations relevant to the
anticonvulsant activity is not clear (White, 1994).
In recent years, several anticonvulsants of potential clinical
importance have been recognized as low-affinity NMDA receptor
channel-blockers. These include dextrornethorphan and its metabo-
lite dextrorphan; ARL 12495 (formerly FPL 12495;1,2-diphenyl-2-
propylamine), Ithe metabolite of the anticonvulsant remacemide; and
the adamantane analog memantine. In contrast to dissociative anes-
thetics, low-affinity channel-blockingNMDA antagonists substitute
poorly, or not at all, for dizocilpine in drug discrimination testing.
This indicates that they may not produce dissociative anesthetic-like
subjective effects (Grant, Colombo, Grant, and Rogawski, unpwb-
lished). Moreover, for dextrornethorphan, dextrorphan,remacemide,
and memantine, substantial clinical experience indicates that the
compounds can be well tolerated in humans. However, adverse
experiences with all of these compounds have been reported (see
Rogawski, 1993). Controlled therapeutic trials will be necessary to
Epilepsy 219

verify the efficacy and safety of these low-affinity, uncompetitive

NMDA antagonists in the treatment of seizure disorders. Neverthe-
less, there is cause for optimism with this class of compounds.
In addition to their potential in chronic epilepsy therapy,
NMDA antagonists may have utility in the treatment of seizures that
occur during ethanol withdrawal (Grant et a!., 1990; Liljequist, 199 I ;
Morrisett et al., 1990).This may be in part because of a compensatory
upregulation in the expression of NMDA receptors after chronic
ethanol exposure (Sanna et al., 1993). ADCI is particularly effective
in this regard (Grant et al., 1992).
3.1.3. GIycine Site Antagonists
It is now well recognized that glycine is a required co-agonist
for activation of the NMDA receptor (Johnson and Ascher, 1987;
Kleckner and Dingledine, 1988). Consequently,agents that competi-
tively antagonize the action of glycine would produce a functional
block of the receptor and could, therefore, have anticonvulsantactiv-
ity. Several classes of antagonists are now known which more or less
sefectively block the glycine site (Huettner, 199I ; Carter, 1992).
With intracerebroventricular administration, several of these com-
pounds protect against various types of seizure activity (Singh et al.,
199 1; Baron et al., 1990;Koek and Colpaert, 1990; Palfreyman and
Baron, 199 1; Bisaga et al., 19933. Recently, Rundfeld et al. ( 1 994)
observed that intraventricular injection of glycine site antagonists
and partial agonists increases seizure threshold in arnygdala-kindIed
rats, an effect not observed with other types of NMDA antagonists.
A similar positive effect of a glycine site partial agonist (D-cyclos-
erine) was observed against kainate-induced seizures (Baran et al.,
1994). These authors suggested that agents active at the glycine site
of the NMDA receptor may be of utiIity in the treatment of seizure
types that are refractory even to other NMDA antagonists.
A significant impediment to the evaluation of glycine site
antagonists in conventional seizure models has been their lack of
CNS accessibility. This problem now seems to have been largely
overcome, but complete studies of the activity of available com-
pounds in animal seizure models have not yet been reported. Initial
220 Rogawski

clues to the development of systemically active glycine site antago-

nists came from the recognition that HA-966 (3-amino-I-
hydroxypyrmlidin-2-one) could be resolved into enantiorners with
distinct pharmacological activities. One enantiomer was a partial,
low-affinity antagonist of the glycine site (Singh et al., 1990;Pullan
et nl., 1990). This R(+)-enantiomer has activity in the electroshock
seizure test when administered intravenously, but its therapeutic
index is poor (Vartanian and Taylor, 1991). However, several ana-
logs have been synthesized with greater potency, selectivity, and
more favorable toxicity properties, such as L-687,4 14 (3R-amino- 1 -
hydraxy-4R-methylpysrolidin-2-one) (Leeson et al., 1990, 1993;
Smith and Meldrum, 1992). Nevertheless, despite intense effort, it
was not possible to produce a compound in this series with suffi-
ciently favorable properties to warrant clinical development.
Another gIycine site partial agonist with anticonwlsant activity
is 1 -aminocyclopropanecarboxyliGacid (ACPC), a particularly high
affinity ligand. ACPC is protective in several seizure models
(SkoEnick eta]., 1989; Witkin and TorEeIla, 199 1; Smith et al., 1993;
Bisaga et al., 19931, but may not be active in the maximal elec-
troshock test. Unlike other glycine site partial agonists with
anticonwlsant properties, ACPC has nearIy full efficacy (about 85%;
Watson and Lanthorn, 19901,thus perhaps accounting for its unusual
spectrum of activity. Indeed, it is surprising that the drug is anti-
convulsant at all.
Recently, certain 5-nitro quinoxaline-2,3-diones were demon-
strated to have highly potent (KI, < 10 Rn?l) glycine site blocking
activity and good central availability when administered systemi-
cally. These compounds also block AMPA receptors, but do so with
several hundred-fold lower potency (Woodward et al., 1993). Two
such compounds, 5-nitro-6-rnethyl-7-chloro-2,3-quinoxali~e
W C Q X ) and 5-nitm-6,7-dimethyl-2,3-quinoxalinedione (MMDX),
have been reported to have activity in the maximal electroshock test
at reIatively low systemic doses (Tran et al., 1994). However, the
extent to which the weak AMPA receptor blocking activity contrib-
utes to the compounds' anticonvulsant effects i s unclear. The related
quinoxalinedione ACEA- 1021 (5-nitro-6,7-dichIoro- 1,4-dihydro-
Epilepsy 221

2,3-quinoxalinedione) has been reported not to substitute for

phencyclidine in drug discrimination testing, indicatingthat this class
of compounds may not produce dissociative anesthetic-like subjec-
tive effects (Balster et al., 1993). It is possible that selective actions
of these compounds at different NMDA receptor subtypes could, in
part, account for the favorable behavioral profile. However, to date,
glycine site antagonists have not been reported to have substantial
subunit selectivity.
A series ofrelated structures-the 3-nitro-3,4-dihydro-2-quino-
lones-have been described with varying degrees of glycine site or
AMPA receptor selectivity. These compounds are based on 7-chloro-
kynurenic acid, a potent glycine site antagonist in vitro, but eliminate
the carboxylic acid group that seems to prevent blood-brain barrier
penetration. One of these, L-698,544, exhibited good systemic activ-
ity as an anticonvulsant (EDSO,13.2 mg/kg?ip) in the DBA/2 mouse
(Carling et al., 1993).Although L-698,544 interacts with the NMDA
(Kh,6.7 pkf) and AMPA (Kk,, 9.2 pM) recognition sites, these inter-
actions occur with somewhat lower affinity than for the glycine site
w.
(ICso, 0.4 1 A prodrug ester of the potent glycine site antagonist
5,T-dichlorokynurenicacid has also been reported to have systemic
nnticonvulsant activity in the DBAI2 mouse (EDSO,62 mglkg, ip;
Moore et al., 1993). Similarly, anotherquinolinoneglycine site antag-
onist MDL 104,653 (3-phenyl4-hydroxy-T-chlor~-quino~in-2[1H]-
one; McQuaid et al., 1992) has been observed to have anticonvulsant
activity, when administered either intraperitoneally or orally, in
DBAJ2 mice (Chapman et al., 1993). Interestingly,high doses of the
compound produced ataxia and sedation, and the therapeutic ratio
was no better than for other NMDA antagonists.
Study of a further series of noncarboxylic acid quinoIinones
resulted in the identification of L-70 1,273 (3-cyclopropyl-ketone-4-
hydroxyquinolin-2[ 1H]-one), with high potency against audiogenic
seizures in DBN2 mice (4.1rngkg, ip; Rowley et al., 1993).This com-
pound has moderately high activity at the glycine site (IC50,0.42m,
but also interacts with the NMDA recognition site (Kbr 3.4 pi%!),
although it is inactive at;AMPA receptors. More recently, a series of
3'-substituted-3-phenyl analogs of the 4-hydroxyquinolinones were
222 Roga wski

discovered with nanomolar binding affinities for the glycine site

(Kulagowski et al., 1994). As i s the case for the parent 3-ketones,
the 3-phenyl substituted analogs show activity at the NMDA recog-
nition site but do not block AMPA receptors. These compounds
appear to be the most potent systemically active glycine site antago-
nists described to date, with El350 values <1 mg/kg in the DBN2
mouse model when administeredeither in~aperitoneallyor orally. It
would appear that these compounds have favorable toxicity charac-
teristics, producing motor impairment only at doses that are substan-
tially higher than those that protect against seizures, but this wiH
require further confirmation. Thus, a variety of potent, and more or
less selective, glycine site antagonists are now available, some of
which have high systemic potency and excellentoral bioavailability.
Tt remains to be determined if these compounds will be superior to
other types of M D A antagonists for seizure therapy. Of particular
interest is the possibility that the additional AMPA receptor blocking
activity of some of the glycine site antagonists may actually provide
enhanced anticonvulsant activity. As discussed in Section 3 . 2 ,
AMPA receptorblockade can confer a powerful anticondsant effect.
3.1-4.Polyamine Site Antagonists
The demonstration by Ransom and Stec (1988) that the poly-
amines spermhe and spermidine enhanced binding of ~HJdizocilpine
to NMDA receptorsin brain homogenates suggestedthat polyarnines
could facilitate gating of the NMDA receptor.Although polyamines
have multiple effects on NMDA receptors (Rock and Macdonald,
1992; Benveniste and Mayer, 19931, a major action is to increase
channel opening frequency via an interaction with a distinct recog-
nition site en the NMDA receptor complex (Williams et al., 1991).
The polyarnine facilitatory effect appears to be mediated by an
increase in the affinity for glycine and also by a distinct glycine-
independent mechanism (Williams et al., 1994;Zhang et al., 1994b3.
There has been interest in developing polyamine site antagonists,but
success to date has been limited.
Two related compounds proposed as polyamine site antagonists
are the neuroprotective agents ifenprodil and eliprodil (SL82.07 15)
Epilepsy 223

(Scatton et al., 1994). Ifenprodil and eliprodil are now we11 recog-
nized to be potent noncompetitive NMDA antagonists both in vitro
and in vlvo. Electrophysiological studies in cultured hippocampal
neurons have demonstrated that ifenprodil produces a complex effect
on gating of the NMDA receptor channel (Legendre and Westbrook,
1991). This action occurs in a manner that is distinct from that of
other NMDA antagonists, but is otherwise poorIy characterized.
Although there is considerableevidence that ifenprodil and eliprodil
can functionally interact with polyarnine effects on the NMDA
receptor, it is unlikely that this occurs at a common recognition site
(Ogita et al., 1992). It has instead been proposed that the polyamine
and ifenprodiEJeliprodi1binding sitesmay share overlapping domains
an the NMDA receptor complex or that the apparent antagonism
occurs because of a functional interaction at distinct sites.
Recently, it has been observed that the distribution of PWIifen-
prodil binding sites in brain closely matches the expression of
NMDAR-2B subunit mRNA (Dana et al., 1991). Moreover, ifen-
prodil appears to selectively antagonize NMDA receptors composed
of NRlA and NR2B subunits, although it can also block NRl A/
NR2A receptors at substantially higher concentrations (Williams,
1993). Therefore, at ordinary doses, ifenprodil may interact with
only a subpopulation of NMDA receptors. Interestingly, it now
appears that polyamine facilitation is variably expressed depending
on the subunit composition of the NMDA receptor. The 2B subunit
is a key subunit in conferring the receptorwith polyarnine sensitivity
(Zhang et al., 1994b).
Despite their relatively potent NMDA receptor blocking activ-
ity, ifenprodil and eliprodil appear to have more favorable toxicity
profiles than other NMDA antagonists (Scatton et al., 1994). At
neuroprotective doses, they do not produce neurological impairment
and do not substitute for phencyclidine in drug discrimination studies
or induce amnestic effects in passive avoidance testing. Moreover,
clinical trials have indicated that the drugs do not produce psycho-
stimulant, amnestic, or psychotomimetic effects in humans. In addi-
tion, eliprodil does not appear to produce pathomorphological
changes, that, as has been noted in Section 3.1.2., are characteristic
 of other NMDA antagonists (Duval et al., 1992). Tt has been sug-
gested that the unique subunit selectivity of ifenprodil and eliprodil
may account for their favorable toxicity characteristics.
As is the case for other M D A antagonists, ifenprodil and
eliprodil have a broad spectrum of anticonvulsant activity in animal
seizure models (De Sarro and De Sarro, 1993; Scatton et al., 1994).
These effects, however, occur at doses that are higher than the
neuroprotective doses and are nearer to the doses that cause toxic
effects. For example, in the case of ifenprodil, there is little separa-
tion in the doses that protect against seizures (mouse maximal elec-
troshock test ED50,29mgkg,ip) and induce motor impairment. For
eliprodil the therapeutic index is somewhatbetter (electmshockED~~,
15 mgikg, ip; rotarod ED501 59 rng/kg). (Interestingly, however,
eliprodil has been shown to potentiate the anticonvulsantactivity of
the competitive NMDA recognition site antagonist CGP 37849;
Deren-Wesolek and Maj, 1993.) Thus,it may be that the NMDA
receptor subtype selectivity of ifenprodil/eliprodilis not optimally
suited for seizure protection, at least in the animal models used for
screening.Whether this is a characteristic of all functionalpolyamine
antagonists, remains to be determined.
A variety of other compounds have been proposed as polyamine
antagonists, including several polyarnines (Williams et al., 1990)
and certain peptide components of marine snail toxins (Skolnick et al.,
1994).Nevertheless, few of these proposed antagonists are suitable
for evaluating the idea that polyamine antagonism is a viable anti-
convulsant strategy. Indeed, several putative polymine site antago-
nists have complex effects on the NMDA receptor, including
channel-blocking activity, which eonfound any interpretation of their
specific polynmine site effects (Donevan et al., 1992; Submmaniam
et al., 1992). However, one interesting candidate antagonist is N-(3-
aminopropy1)cyclohexylamine (APCHA), a cyclohexyl diamine. It
has been demonstrated to block the facilitation by spermidine of
NMDA-induced seizures in mice (Chu et al., 1994). Unfortunately,
APCHA may not be active with systemic administration and it has
yet to be demonstrated that this compound acts via a specific inter-
action with the polyamine site.
Epilepsy 225

There is some evidence that brain polyamine concentrations may

increase with kindling, either produced electrically (Hayashi et al.,
1989) or by repeated treatment with pentylenetetrazol (Hayashi et
al., 1993). However, it remainsundetermined whether these increased
levels contribute to the hyperexcitability of the kindled state. Should
this be the case, the argument supporting the potential use of
polyamine site antagonists in seizure therapy would be strengthened.
3.1.5. An fagovtists rat Ofher Sites on the NMDA Receptor Complex
and the Combined Acfions of Felbamate
on NMDA/GABA, Recep f ors
In recent years, a class ofNMDA antagonist has been identified
in which inhibition is exerted at sites that are distinct from those of
known NMDA receptor coagonists or facilitatory modulators.
Indeed, ifenprodiI and eIiprodil are probably best considered among
this class of NMDA antagonist. Other examples include a series
of n-alkyl diamines that inhibit NMDA receptors by acting at a
nonvoltage dependent, hydrophobic binding site as well as in n chan-
nel-blocking fashion (Subramaniam et al., 1994). Similarly, the anti-
convulsant rernacemide may also block NMDA receptors in part by
such an allosteric action (Submmaniam et aI., 1995a). Felbamate too
is an example of an anticonvulsant that may antagonize NMDA
receptors by an allosteric effect on channeI gating, although a fast
channel-blocking action of the drug may be more important.
Although glycine and the glycine site agonist d-serine are able to
functionally reverse the anticonwlsant effects of felbamate in vivo
(Hamsworth et al., 1993; Coffin et al., E 994), there is strong evi-
dence that felbamate does not act directly at the glycine site (Rho et aI.,
1994d; Subramaniam et al., 1995b).
As discussed in Section 2. I .2., felbamate also produces a mod-
est potentiation of GABAAreceptor responses within the same range
of concentrationsthat it blocks NMDA responses (Rho et al., 1994b3.
Both of these effects occur at concentrationsof felbamate likely to be
present in the brain during antiepileptic therapy. Felbamate exhibits
a broader spectrum of anticonvulsant activity than conventiona1
antiepileptic agents such as phenytoin and carbamazepine. (It con-
226 Rogawski

fers protection in the maximal electroshock test and also against

seizures induced by pentylenetetrazol; Swinyard et al., 1986.) Clini-
cally, the drug has activity in the treatment of partial and secondarily
generalized tonic4onic seizures and it is also effective against
refractory seizures of the Lennox-Gastaut syndrome in children,
which are notoriously difficult to treat. The combination of actions
of felbamate on excitatory and inhibitory synaptictransmissioncould
account for its broad spectrum of activity and favorable side-effect
profile. More specificaIly, it can be postulated that the distinct
actions on NMDA and GABAAreceptors are by themselves below
the threshold for side effects, but that the actions at the two sites are
additive or even synergistic against seizures. That a drug such as
felbamate with low neurological toxicity may exert its therapeutic
activity v i a low-affinity interactions with more than one receptor
system contradicts the conventional view that side-effect reduction
is best achieved by high selectivity and potency. However, for
anticonvulsantdrugs that modulate excitability mechanisms criti-
cal to normal brain function, agents with high potency and efficacy
may have unacceptable toxicity. (See Section 2.1.1.1. for a more
detailed discussion with reference to partial benzodiazepine receptor
agonists.) Therefore, the search for drugs that exert low efficacy
effects on more than one receptor seems to be a worthwhile strategy.
3.2. RMPA Receptor Antagonists
AMPA (non-NMDA) receptors play a key roIe in CNS integra-
tion as the prime mediators of fast synaptic excitation. The critical
nature of AMPA receptors is hard to overstate inasmuch as they
participate in virtually every central circuit and, of particular impor-
tance here, mediate epileptiform activity in a variety of model sys-
tems (Rogawski, 1994). Consequently, the observation that AMPA
receptor antagonists have anticonvulsant activity is not unexpected.
However, at present, it is unclear if AMPA receptor antagonists
will be sufficiently free of toxicity to be clinically useful anti-
convulsants. Nevertheless,the possibility of selectivelytargeting the
various AMPA receptor subtypes provides enormous opportunities
for drug development.
Epilepsy 227

3.2.1. CornpstifiveAMPA Receptor Anfagonisfs

During the early period of excitatory amino acid receptor

research, AMPA receptor antagonists were unavailable. However, in
the late 1980s the situation changed: Hanore et al. ( 1988) deveIaped
a series of quinoxaiinediones as selective and relatively potent
competitive AMPA recognition site antagonists (see Davies and
CoIlingridge, 1990). Although the first quinoxalinediones to be
described were not systemically active, compounds with good
systemic bioavailability are now available. These include the benzo-
h s e d quinoxnlinedioneNBQX C2,3 -dihydroxy-6-nitro-7-sul famoyl-
benzo[F]quinoxaline; Sheardown et al., 1990) and the 6-irnidazol
substituted quinoxaIinedione YM90K (6-[lH-imidazal-1-yll-7-
nitro-2,3-[1H-4~-quinoxalinedione; Ohmori et al., 1994) that may
have improved CNS penetration in comparisonwith NBQX. A series
of isatin oxamines has also been described which are highly selective
AMPA receptor antagonists (Watjen et al., 1993). These compounds
have anticonvulsant activity against AMPA-induced seizures
following intravenous and oral administration. In addition, a substi-
tuted decahydroisoquinoline-3-carboxylicacid has been recently
described with good systemic AMPA receptor blocking activity
(Omstein et al,, 1993). This compound, LY 2 15490 ([3SR,4aRS,
4RS,8aRS]-6-[2-(1H-tetrazol-5-yl)ethyl]decahydroisoquinoline-3-
carboxylic acid), also interacts with the NMDA recognition site, but
with 5- to 10-fold lower potency.
Competitive AMPA recognition site antagonists are protective
in the maximal electroshock test and against seizures induced by
various chemoconvulsants (Yarnaguchi et al., 1993; Omstein et al.,
1993). In addition, these compounds have activity against reflex
seizures in rodents and primates (Chapman et al., 1991; Smith et al.,
1991;Meldrum et al,, 1992; Ohmori et al., 1994). In the kindling
model, NBQX has been reported to have protective activity, although
it is less potent than in other seizure models (Lbscher et al., 1993).
This is in sharp contrast to NMDA antagonists which are weak or
ineffective against established kindled seizures. Despite its activity
against kindled seizures, NBQX has no effect on the development of
 kindling (DiirmiiIler et aI., 1994). This is another important differ-
ence from NMDA antagonists, which, as has already been noted
(Section 3.1 .), do protect against kindling devejoprnent.
It has ggnerallybeen found that AMPA receptor antagonists have
neurological, toxicity at anticonvulsant doses, although this varies
depending on the seizure mode1 and test conditions < w e Chapman
et al., 199I). Thus, NBQX produced motor impairment at doses that
are similar to those that are protective in the maximal electroshock
test (Yamaguchi et al., 1993). The LY215490 has only a modestly
better therapeutic ratio (=2.2) (Omstein et al., 1993). Nevertheless,
it would be premature to conclude that AMPA receptor antagonists
are unlikely to have clinical utility in seizure therapy, since block-
ade of AMPA receptors is an entirely new therapeutic strategy. Only
through clinical trials will it be possible to assess the significance
of the therapeutic ratio values determined from animal testing.
Lascher et al. (1993) observed that low doses of NMDA receptor
antagonists synergistically enhance the anticonvulsant activity of
NBQX in the kindling model, without producing anincreasein adverse
effects. Although the basis of this phenomenon is poorly understood,
it seems reasonable that a combination of NMDA and AMPA receptor
blockade may ultimately prove to be the optima1 approach for epilepsy
therapy. In fact, Iow levels of NMDA receptor blockade may provide
an antiepileptogenic effect and may also protect against seizure-
induced brain damage, in a manner not obtained with AMPA receptor
antagonists (Berg et al., 1993). As discussed in Section 3.1.3., many
of the recently described gIycine site antagonists also have various
degrees o f AMPA receptor blocking activity. It will be of interest
to determine if the combined activities provide cEinically superior
therapeutic activity with acceptable side-effect properties.
Another potential approach to obtaining improved anticon-
vulsant activity with a reduction in side effects would be to target
AMPA receptor subtypes specifically involved in seizure genera-
tion or propagation. Such putative seizure-related AMPA receptor
subunits have yet to be identified. However, there is evidence that
non-NMDA receptors can be selectively targeted with antagonists.
Thus, the isatin oxime NS- 102 (5-nitro-6,7,8,9-tetmhydrobenzo-
Epilepsy 229

k]indale-2,3-dione-3-oxime) is a non-NMDA antagonist with selec-

tivity for the kainate binding subunit GluR6 (Johansen et aI., 1993;
Verdoorn et al., 1994). However, the anticonvulsant profile of this
compound remains to be determined.
3.2.2. NoncornpefitiveAMPA Receptor Antagonists
A novel class of selective AMPA receptor antagonists has
recently been identified that exert their blocking action in a mecha-
nistically distinct fashion from competitive AMPA recognition site
antagonists. These antagonists-typified by the 2,3-benzodiazepine
(homophthalazine) GYM 52466 (1-14-aminophenyll-4-methyl-7,8-
methylenedioxy-5H-2,3-benzsdiazepine)-offer an alternative
approach for blockade of AMPA receptors with potentially distinc-
tive consequences (Tarnawa et al., 1990; Ouardouz and Durand,
1991;Jones et al., 1992). GYKl52466, unlike the quinoxalinedione
AMPA antagonists, does not interact with the AMPA recognition
site, nor is it a channel blocker. Rather, it appears to block AMPA
receptors in a noncompetitivefashion via anovel allosteric site on the
AMPAreceptorcomplex (Doncvanand Rogawski, 1993). The block-
ing action of GYKl52466 is highly selective in vitro, with essentially
no effect on NMDA, metabotropic glutamate, or GABAAreceptor
responses, The lack sf effect on GABAA receptors is particularly
notable in view of the structural similarity of GYKI 52466 with
conventional 1,4-benzodiazepines(see Section 2.1. I .).
Like competitive AMPA recognition site antagonists, GYKl
52466 has anticonvulsant activity in a broad spectrum of animal
seizure models (Chapman et al., 199 1; Smith et al., 1991;Yamaguchi
et al., 1993; Steppuhn and Turski, 1993). In some experimental
models, GYKI 52466 has improved anticonvulsant activity corn-
pared with NBQX. In others, NBQX appears to have greater
selectivity and potency. One situation where the noncompetitive
antagonists would theoretically be preferable to competitive antago-
nists is in protection against seizures associated with high synaptic
glutamate levels (see Rogawski, 1993). Under these conditions, the
synapticallyreleased glutaman would surmount the blocking action
of a competitive antagonist so that high doses of the antagonist would
 be required to confer seizure protection. However, these high doses
would be more likely to induce side effects. In contrast, minimal
doses of drugs Iike GYKX 52466 may be effective, since equivalent
degrees of block are achieved whatever the glutamate level.
A series of N-substituted GYKE 52466 analogs has been
described with varying degrees of AMPA receptor blocking activity
(Tarnawa et al., 1993). Two of these analogs with greater in vitro
AMPA receptor blocking potencies were found to have correspond-
ingly greater invivo anticonvulsantpotencies(Donevanet al., 1994).
This supports the view that the anticonvulsant activity of the 2,3-
benzodiazepines is due to AMPA receptor blockade.
Recently, it has been demonstrated that AMPA receptors con-
taining the GluR2 subunit have a linear or outwardly rectifying
current-voltage relationship and a low permeability for Ca2+.Com-
binations lacking GluR2 are inwardly rectifyingand have a high Ca2+
permeability (Hume et al., 1991; Hollrnann et al., 1991; Verdoorn
et al., 199 I). GYKI 52466 appears to block Ca2'-permeable and Ca2+-
impermeable AMPA receptors with equal potency (Donevan and
Rogawski ,unpublished). This is in contrast to the barbiturate pento-
barbital that selectively blocks Ca2+-impermeableAMPA receptors
(Taverna et al., 1994) and certain arthropod toxins that are selective
for Ca2+-permeableAMPA receptors (see Section 3.2.3 .). Interest-
ingly, GYKI 52466 and its analogs appear to have much higherblock-
ing potency for AMPA-selective non-NMD A receptor subunits than
for kainate p r e f m g subunits (Patemain et a]., 1995).The implications
of these various selectivity differences are not yet well understood.
3.2.3. Channel-Blocking AMPA Recepfor Antagonists
At present, no selective channel-blocking AMPA receptor
antagonists have been identified. However, certain polyamine
arthropod toxins could provide clues to the development of such
compounds. The toxins (such as argiotoxin 636, philanthotoxin, and
Joro spider toxin) act as potent noncompetitive antagonistsof verte-
brate AMPA receptors (Brackley et al., 1993; Blaschke et al., 1993).
These toxins act in a use- and voltage-dependentmanner suggesting
that they are channel blockers (Herlitze et al., 1993). However, the
Epilepsy 231

toxins are not selective for AMPA receptors, and indeed their block
ofNMDA receptors is more reliable and often more potent (Priestley
et al., 1989; Ragsdale et al., 1989). A likely reason for the inconsis-
tency ofthe AMPA blocking action is suggested by the recent discov-
ery that the polyamine toxins selectively block inwardly rectifying
AMPAreceptors (that is, those that lack the Glum subunit)(Blaschke
et al., 1993; Herlitze et al., 1993).
From the point ofview of their use as pharmacological tools, the
fact that the toxins block both NMDA and AMPA receptors is a
disadvantage. However, this may not be an obstacle to the use of such
compounds as therapeutic agents. As has. been noted previously,
combined NMDAIAMPA receptor blockade may produce a syner-
gistic anticonvulsant effect. Moreover, the seIectivity of the toxins
for inwardly rectifying AMPA receptors may be a distinct advantage.
Since rectifying AMPA receptors are Ca2+permeable, it is not hard to
imagine that they could play a role in seizure generation or in the
neurotoxicity associated with prolonged seizures. In fact, there is sug-
gestive, but by no means conclusive, evidence in support of both pos-
sibilities. Thus, it has recently been reported that amygdaloid kindling
is associated with a 25-30% reduction in Glum levels in the limbic
forebrain and pirifom coflexlamygdala (but not in the entorhinal cor-
tex or amygdala; Prince et al., 1995). The decrease-which was spe-
cific for the GluW subunit-was observed in kindled animals at 24 h
after the last seizure; GluR2 levels had returned to normal at 1 wk and
1 mo.Similar changes were not obtained after induction of seizures
with the convulsant pentylenetetrazol. It is conceivable that the
decrease in Glum could be a factor in the induction, but not the main-
tenance, of kindled seizures. If this is the case, agents such as the
polyarnine toxins which selectivelyblock AMPAreceptors lacking the
Glum subunit could have interesting antiepileptogenic potential.
An additional Iine of experimentation is consistent with the
possibility that GluR2 subunit downreguIation could play a role in
seizure-induced neuropathology.Thus,Friedman et al. ( 19943 recently
reported that persistent seizure activity (status epilepticus) can result
in reduced expression of the GluR2 subunit in hippocampal regions
most vulnerable to neurodegeneratian. This reduction occurs with a
time course that parallels the neuronal cell loss, supporting a role for
Ca2+permeable AMPA receptors in the seizure-induced pathology.
Polyamine toxin- li ke agents with specificity for Ca2+-permeable
AMPA receptors might, therefore,be well suited as neuroprotectants
to ameliorate seizure-induced pathological changes.
Although only limited information is available, polyarnine tox-
ins and a series of smaI1 mol wt analogs referred to as "araxins" do
have anticonvulsant and neuroprotective activity when administered
intracerebroventricularly or systemically (Seymourand Mena, 198 9;
Mueller, personal communication). At therapeutically effective doses,
the compounds do not appear to produce dissociative anesthetic-like
behavioral or histopathological effects, and do not generalize to
phencyclidine in drug discrimination studies. However, with systemic
administmtion,rhereis poor separationbetween the doses that confer
seizure protection and induce neurological impairment. In addition,
the toxins may produce significant cardiovascular side effects.
3.3. Metaboiropic Glutamate Receptors
Metabotropic glutamate receptors are a diverse group of G-
protein-coupled receptors that are structurally and functionally dis-
tinct from other glutamate receptors (Suzdak et al., 1994). In contrast
to NMDA and AMPA receptors which are themselves ion channels,
rnetabotropicglutamate receptors act via various second messengers
to indirectly regulate a wide variety of ion channels. The potentia1
role of metabotropicglutamatereceptorsas targets foranticonvulsant
drugs is not well defined. Nevertheless, activation of rnetabotropic
glutamate receptors with selective agonists can produce, in adult
rodents, limbic-like seizures similar to those observed in kindled
animals (Sacaan and Schoepp, 1992;Tizzano et al., P 994). In neona-
tal rats, metabotropic agonists can produce frank convulsions
(McDonald et al., 1993).Interestingly,however, low doses ofcertain
metabotropic glutamate receptor agonists can have weak anti-
convulsant effects (see Thornsen et al., 1994). The anticonvulsant
effects presumably arise because the rnetabotropic glutamate recep-
tor agonists reduce glutamate release by a presynaptic action on
inhibitory autoreceptors (Glaum and Miller, 1994).
 Recently, a novel series of conformationally restricted phenyl-
gIycine analogs have been described which act as competitive antag-
onists of at least some metabotropic glutamate receptors (Birse et ai.,
1993; Thornsen and Suzdak, 1993; Ferraguti et al., 1994). One of
these compounds, IS)-4-carboxy-3-hydroxyphenylglycine ([SJ-
4C3HPG), has been reported to protect against audiogenic seizures
in DBA/2 mice at doses that do not produce neurological impaiment
(Thornsen et al., 1994). This effect occurred with intraventricdar,
but not systemic, administration of the drug. In addition,(S)-4C3HPG
diminished the epileptiform activity observed in rat cortical slices
exposed to Mg2+-freeconditions. L-AP3 (L-2-amino-3-phosphono-
propionate), a low potency noncompetitive metabotropic receptor
antagonist(Schoepp, 19941, has also produced a weak anticonvulsant
effect folIowing intraventricular administration (Klitgaard and Jack-
son, 1993). Bath IS)-4C3HPG and L-AP3 can have rnetabotropic
glutamate receptor agonist properties under some circumstances
(Birse et al., 1993).It is therefore conceivable that the anticonwlsant
activity of these compounds relates, at least in part, to this agonist
activity, possibly by presynaptic effects an glutamate release. Indeed,
it is not clear at present whether metabotropic receptor agonism,
antagonism, or a combination of agonist and antagonist effects at dis-
tinct metabotropic receptor types represents the most effective
anticonvulsant approach. NevertheIess, targeting of the various
metabotropic receptor types with selective agonists and antagonists
provides interestingopportunitiesfor anticonvulsantdrug development.
3.4. Glutanrate Release Inhibitors
Metabotropic glutamate receptors axejust one example of a host
of receptors and ion channels of the glutamatergic nerve terminal
that are attractive anticonvulsant targets. It has aiready been noted
that barbiturates might in part exert their anticonvulsant activity via
inhibition sf glutamate release (through effects on voltage-depen-
dent Ca2+channels). In addition, as discussed in the next section, the
therapeutic effects of anticonvulsant drugs that interact with voltage-
dependent Na' channels is likely due to some extent to inhibition of
glutamate release. It appears that certain toxins including o-Agn
IVA and cs-Aga MVIIC, which block Ca2+channels in presynaptic
nerve terminals can have anticonvulsant effects when administered
inbacerebroventricularly (Jackson et al., 1994). Moreover, a series
s f novel N,N'-diarylguanidines have been reported to be potent, sys-
temically active glutamate release blockers although their mecha-
nism of action i s not well understood (Reddy et aI., 1994). There are
thus a number of interesting leads to glutamate release antagonists of
potential clinical utility. The challenge will be to develop agents that
have sufficiently low toxicity to be useful in seizure therapy.
4. Interactions
with Voltage-Dependent Nat Channels
A wide variety of anticonvulsant drugs are believed to act, at
least in part, via their effects on voltage-dependent Na* channels.
Phenytoin is perhaps the best studied example. Phenytoin is a reia-
tively weak Na* channel blocker and its ability to inhibit Na+channel
activity is highly dependent on the state of the channel. Therapeutic
concentrations of the drug have little activity on resting Na'channels
at hyperpolarized membrane potentials. Thus, at a potential of -80
mV, 10 p M phenytoin, a concentration at the high end of the range
of free therapeutic plasma levels, would produce no more than 1 5%
block of Na' current (Lang et a!,, 1993). However, there is more
significant block when Na' channels are repetitively activated or
when the initial membrane potential is at a more depolarized level.
These properties are believed to reflect the higher affinity of
phenyrain for activated and inactivated channels than for resting
channels (Ragsdale et al., 1991). During high frequency firing, there
is aprogressiveaccumulationof drug binding as Na*channels cycle
through the activated and inactivated states with each action poten-
tial. In addition, a greater proportion of Na+channels is in the inacti-
vated state at depolarized membrane potentials, thus accounting
for the voltage dependence of block. Thc rate at which phenytoin-
bound Na+ channels recover from inactivation is markedly slowed,
particularly at depolarized potentials (Schwartz and Grigat, 1 989;
Kuo and Bean, 1994). This property accounts for the stabilization of
Na+channels in the inactivated state.
Epilepsy 235

The precise way in which a modification of Na+channel gating

results in seizure protection is not we11 understood. However, the
following hypothesis has often been proposed. During seizures, neu-
rons fire more rapidIy and are more depolarized than under normal
conditions, so that their Na* channels would be more susceptible to
block. This would allow phenytoin to selectively suppress high fre-
quency firing. Indeed, at low concentrations, phenytoin is well known
to produce a selective inhibition of repetitive action potential firing,
whereas single action potentials are resistant (McLean and
Macdonald, 1983). The effects of phenytoin an Na* channels may
ultimately translate into reduced glutamate-mediated synaptic exci-
tation, and this cousd play an important role in its anticonvulsant
activity. In fact, phenytoin inhibits the release of various neurotrans-
mitters, including glutamate from brain slices stimulated by the Wa*
channeI activator veratrine (Leach et al., 1986).
A wide variety of anticonvulsant drugs have a spectrum of
anticonwlsant activity in animal seizure models simiIar to that of
phenytoin (Rogawski and Porter, 1990). Many of these may also act
via an interaction with Na+ channels, and in several cases this has
been confirmed in vitro. For example, lamotrigine, an anticanvuEsant
effective in the treatment of refractory partial seizures (Yuen, 1994),
has a similar profile to phenytoin; it is protective in the maximal
electroshock test but not against pentylenetetrazol-induced clonic
seizures (Miller et al., 1986). At clinically relevant concentrations,
lamatrigine has been shown to block repetitive firing of CNS neu-
rons. This effect can be reversed by hyperpolarization of the resting
membrane potential, in a manner similar to that of phenytoin (Cheung
et aI., 1992). In addition, the drug suppresses burst firing m cortical
neurons (Lees and Leach, 1993),and inhibits binding of [3M]batracho-
toxinin A 20-a-benzoate, a Iigand for Na*channels, to rat brain synap-
tosomes (Cheung et al,, 1992). In voltage clamp studies, Iamotsigine
produced a use-dependent inhibition of Na+channels and slowed the
rate of recovery from inactivation, effects similar to those produced
by phenytoin (Lang et al., 1993; Taylor, 1993). Thus,the similarity
between larnotrigine and phenytoin in animal seizure modeIs is par-
alleled by corresponding actions on Na* channels.
236 Rogu wski

Riluzole is another anticonvulsant drug with a phenytoin-like

spectrum of activity (Mizoule et al., 1985).(Riluzole also has neuro-
protective properties [see, for example, Wahl et al., 19933 as does
phenytoin [Stanton and Moskal, 1991; Hayakawa et al., 19941.)
Among its various pharmacological actions, riluzole is a blocker of
voltage-dependent Na+ channels. Interestingly, however, unlike
phenytoin, the block produced by riluzole does not occur in a use-
dependent fashion, suggesting that it does not preferentially bind to
activated Na+ channels. Rather, riluzole has an exceptionally
high (>150-300-foId) selectivity for the inactivated state of the
Nat channel (Benoit and Escande, 1991). These results with
riluzole indicate that stabilization of the inactivated state of the Na+
channel may be a particularly critical factor in the anticonvulsant
activity of phenytoin.
Several other anticonvulsant drugs with a phenytoin-Iike spec-
trum of anticonvulsant activity interact with Na+channels in a fash-
ion similar to phenytoin. These include carbamaqine (Ragsdale et al.,
1991; Lang et al., 1993), ralitoline (Rock et al., 1991; Fischer et al.,
1992), and flunarizine (Kfskin et al., 1993). In addition, the antican-
vulsant U 54494A (3,4-dichloro-N-methyl-N-[2-(1 pyrraIidiny1)-
cyclohexylJbenzarnide)(Zhu and Im, 1992), its two major active
metabolites (Zhu et al., 1993); and several other structurally related
benzarnides with anticonvulsant properties (Zhu et al., 1992) have
been s h o w to interact with Na' channels in a voltage- and use-
dependent fashion, similarlyto phenytoin. The success in identifying
phenytoin-Iike anticonvulsantsis probably a result of the widespread
use of the maximal electroshock test as a screening method (inas-
much as the test is highly sensitive to such agents). Since there are
already a large number of safe and effective anticonvu1sant drugs of
this type, the development of additional phenytoin-like compounds
may not seem be a high priority. However, it would be reasonable to
search for drugs that produce phenytoin-like effects in combination
with other pharmacological activitiesthat result in seizure protection
(for example, potentiation of GABA or inhibition of excitatory amino
acid transmission). The major acute neurologica1 doxicity of
phenytoin is xeferabIe to cerebellar dysfunction, possibly because
Epilepsy 237

cerebellar neurons are among the most rapidly firing in the CNS and
are therefore particularly susceptibleto use-dependentblock. Differ-
ent types of acute toxicities are produced by anticonvulsant drugs
acting on other targets. For example, GABA-potentiatingdrugs typi-
cally produce sedation, an effect not usually seen with phenytoin.
Thus, by combiningNa'channel blocking activitywith anotheraction
it may be possible to produce enhanced anticonvulsant effects with-
out a corresponding increase in toxicity,
5. K+ Channel Opener Drugs
Like GABAAreceptors, the fundamental role of Kichannels is
to dampen excitability. Consequently, drugs that enhance the activity
o f K*channels are reasonable antiepileptic drug candidates. Activa-
tion of K+channels would be expected either Ea hyperpolarize neu-
rons and thus inhibit them or to limit action potential firing by
increasing the opposing influence that K+currents have on depalas-
izing Na* currents.
In recent years, a diverse group of molecules have been identi-
fied that are capable of opening K' channels in excitable cells.
Research in this area began with the discovery that the antihyper-
tensive benzopyran cromakalim relaxed vascular smooth muscle by
opening K+channels (Weston and Edwards, 1992). Subsequently, it
was recognized that several other structurally dissimilar antihyper-
tensive agents, including diazoxide, minoxidil, and pinacidil, were
also K+channel openers. These studies with existing compounds led
to the synthesis of a large number of novel K+ channel openers
(Robertson and Steinberg, 1990).
There are a great variety of K+channels in neuronal cells and a
corresponding diversity in their functional roles. Consequently, in
characterizing the pharmacological effects of a K+channel opener
drug, it is of critical importance to define the type of K+channels
modulated by the drug. The range of K+channel types sensitive to K+
channel opener drugs is still incompletely defined. It may be that the
channel types affected depend on the specific drug and tissue exam-
ined. For example, the benzimidazolone NS 004 (1 -[2-hydroxy-5-
chlorophenyl]-5-trifluaromethyl-2-benzimidazolone)is said to
Epilepsy 239

ATP levels in substantia n i p neurons that would activate GTPchan-

nels and depress GABA release. The overall effect would be to obvi-
ate the critical role played by the substantia nigra in the control of
seizure spread (Gale, 1985, 1992). In hypoglycemia, reduced blood
glucose would also lead to diminished intraceilular ATP levels and
a similar inactivation of the substantia nigm seizure-control mecha-
nism, perhaps contributing to hypoglycemic seizures.
In other brain regions such as the hippocampus, Knw channel
activation could serve to inhibit seizure activity. Thus, cromakalim
reduced bursting of hippocampa1 neurons in the in vitro slice prepa-
ration (Alzheirner and ten Bruggencate, 1988) and in cell culture
(Simon and Lin, 1993). However, in other situations the drug failed
to affect hippocampal epileptiform discharges, although it was able
to inhibit the response to anoxia (Mattia et al., I 994). There are a
few reports that intraventricnEarly administered cromakalim can
protect against seizures in certain in vivo chemoconvulsant models
(Gandolfo et al., I989a,b; Del Pozo et al., 1990; Popoli et al., 1991),
but these reports require confirmation with more traditional anti-
convulsant screening tests. As of yet, no K* channel opener drug has
been demonstrated to have CNS activity following systemic adrnin-
istration. Recently, however, benzopyrans structuraIly related to
cromakalim have been described with oral anticonvulsant activity in
the maximal electroshock test (Evans et al., 1992). Whether this
anticonvulsant activity occurs as a result o f effects on K+channels
remains to be determined.
The Ktchannel opener drugs represent an interesting direction
for anticonvulsant drug development. However, there are a number
of impediments that must be overcome before this strategy can be
considered seriously. As noted, blood-brain barrier permeable ana-
logs are required. Assuming such compounds become available,
nonselective K+ channel opener drugs could theoretically have
proconvulsant effectsmediated, for example, by the substantia nigra.
In addition, there is evidence that some K+channel openers can block
certain voltage-dependent K+ channel types that might predispose to
seizures (Politi et al., 1993).Atpresent, the potential utility of K+chan-
nel opener drugs in epilepsy therapy is uncertain.
 Interestingly, however, there are a few reports in the literature
that suggest that presently available anticonvulsant drugs may act by
enhancing K* channel function. For example, it has been proposed
that the tetronic acid derivative losigamone could protect against
seizures by such a mechanism (Klihr and Heinemann, 1990). In
addition, there is a report indicating that carbamazepine may enhance
a K+ current in neocortical neurons (Zona et al., 1990), However,
until further confirmatory data is obtained, these observations must
be considered preliminary.

6. Adenosine Agonists
and Release-EnhancingAgents
Adenosine is a powerful endogenous inhibitory neuro-
modulator that is normally present in the extracellularenvironment
at a concentration of about 1 ph4 (Zetterstrorn et al., 1982; Greene
and Haas, 1991). Adenosine exerts its inhibitory action on CNS
excitability by direct (postsynaptic) hyperpolarization of neurons
and by inhibition of synaptic release, particularly of glutamate, via
adenosine receptors on excitatory nerve terminals (Proctor and
Dunwiddie, 1987). These actions are primarily mediated by aden-
osine receptors of the A1 type (McCabe and Scholfield, 1985). Dur-
ing seizure activity, adenosine levels increase dramatically, which
has led to the proposal that the adenosine may mediate seizure
arrest and postictal refractoriness (Lewin and Bleck, 1981;
Dragunow, 1986; Whitcomb et al., 1990; During and Spencer,
1992). A recent study in the hippocampal dice preparation has
suggested that glutamate acting on NMDA receptors can stimulate
adenosine release from interneurons (Manzoni et al., 1994). How-
ever, the extent to which this accounts for the adenosine released
during seizures in the hippocampus or elsewhere remains uncer-
tain. Evidence that endogenous adenosine release protects against
seizure activity is the well-known proconvuIsant activity of
adenosine AI antagonists (Albertson et al., 1983; Murray et al.,
1985). Conversely, treatments that increase adenosine levels or its
actions on inhibitory mechanisms may be effective in preventing
Epilepsy

seizures. For example, studies in a hippocampal slice preparation

have demonsbated that adenosine can suppress epileptifom activity
(Dunwiddie, 1 980; Lee et al., 1984; Ault and Wang, 19X6),whereas
blockade of adenosine receptors induces sustained interictal dis-
charge and seizure-like activity (Thompson et al., I 992; Alzheimer
et al., 1993). There is evidence that adenosine selectively depresses
excitatory but not inhibitory synaptic transmission (Yoon and
Rothman, 199 1; Thompson ct a]., 1992;Katchman and Hershkowitz,
1993). The selectivity for excitatory transmission provides a mecha-
nism for adenosine's superior anticonvulsant activity in comparison
with other presynaptic modulators (for example, GABABagonists)
that may reduce inhibitory as well as excitatory synaptic events.
Much evidence from in vivo experimental models demonstrates
that adenosine receptor stimulation can modulate seizure activity.
Adenosine itself has weak anticonvulsant propeaies because it has
an extremeIy short biological half-life (5-6s) and probably pen-
etrates the blood-brain barrier poorly (Rudolphi et al.. 1992).Never-
theless, adenosine can protect against audiogenic seizures in mice
(Maitre et al., 1974)and also prolongs the latency to pentyleneeetrazol
seizures (Dunwiddie and Worth, 1982). Selective adenosine A 1
receptor agonists-such as L-phenylisopropyladenosine, cyclo-
hexyladenosine, and 2-chloroadenosine-have much greater anti-
convulsant potency. These compounds have been reported to have
activity in the maximal electroshock test (Wiesner and Zimring,
1994). In addition, they protect against seizures induced by pentylene-
telrazol (Dunwiddie and Worth, 1982; Murray et al., 1985); bicu-
cullfne (Zhang et al., 1994); penicillin (Niglio eta]., 1988); DMCM,
a benzodiazepine receptor inverse agonist (Petersen, 1991);
hornocysteine, a putative adenosine sequestering agent (hlarangss
et aI., 1990); and 4-aminopyridine (Jackson et aI., 1994). In addition,
adenosine agonists prevent the development of kindling induced by
electrical stimulation of the amygdala (Dragunow and Goddard,
1984) or by the j3-carboline FG 7142 (Stephens and Weidmann,
1989). In contrast, adenosine agonists have variable activity against
seizures in fully kindled animals (Barraco et al., 1984; Rosen and
Berman, 1985). Conventional anticonvulsant drugs generally do not
 interfere with kindling development, although NMDA antagonists
have a paweAl antiepileptogeniceffect (see Section 3.1 .). Thus, the
ability of adenosine agonists to prevent kindling development could
be related to their inhibition of excitatory amino acid release and a
consequent reduction in the activation of NMDA receptors.
Despite the effectiveness of adenosine A1 agonists in animal
seizure models, it is unlikely that these compounds would be clini-
cally useful anticonvulsants. Adenosine Al agonists have powerfuI
cardiovascular effects as a result of their actions on peripheral
adenosine receptors in the heart and vascufature. Even iftheseperiph-
era1side effectscouldbe overcome(for example by coadministratian
of a blood-brain barrier impermeable adenosine antagonist such as
8-p-sulfophenyltheophylline), adenosine agonists at anticonvulsant
doses may produce strong sedative effects that would limit their
clinical utility (Dunwiddie and Worth, 1982). Consequently, alterna-
tive strategies wilt need to be developed. One approach is to utilize
inhibitors of adenosine inactivation. These may specifically target
epileptic brain regions since seizure activity is accompaniedby local
release of adenosine. Such agents would theoretically potentiate the
protective effects of adenosine where needed, without producing
untoward side effects (since release of adenosine may be less signifi-
cant under nonepileptic conditions). There are multiple nucleoside
transport (uptake) systems in brain that inactivate released aden-
osine. Electrophysiological studies in the brain slice preparations
have indicated that adenosine uptake inhibitors such as dipyridamole,
dilazep, nitrobenzylthioguanosine, nitrobenzylthioinosine, hexa-
bendine, and soluflazine can potentiate the inhibitory effects of
exogenous adenosine (Sanderson and Scholfield, 1986; Ashton et at .,
1987) and reduce epileptiform activity (Ashton et al., 1988). How-
ever, adenosine uptake inhibitors generally have little effect on nor-
mal synaptic transmission. Moreover, microinjection of several
adenosine uptake inhibitors into the rat prepiriform cortex reduced
bicuculline-induced seizures (Zhang et al., 1993). n u s , adenosine
uptake inhibition is a potentially promising anticonwlsant strategy,
However, the available adenosine uptake inhibitors are generally of
low potency or do not penetrate the blood-brain barrier. Another
 Epilepsy 243

approach to selectively enhance endogenous adenosine levels is to

inhibit adenosine metabolism with, for example, inhibitors of aden-
osine kinase (such as 5'-amino-5'-deoxyadenosine) or adenosine
deaminase (such as 2'-deoxycoformycin). Although such enzyme
inhibitors have anticonvulsant activity when injected locally (Zhang
et a!., 19931, there is no evidence that they are effective with systemic
administration. Finally, the purine precursor 5-amino-4-irnidazole
carboxarnide riboside (AICAr) (which increases adenosine levels
during ATP catabolism, as may occur in a seizure focus), has weak
anticonvulsant activity that can be enhanced by the adenosine uptake
blocker mioflazine (Marangos et al., 1990). AICAr has low bloo&
brain barrier permeability; it will be necessary to develop analogs
with improved bioavailability before evaluating the potential of this
approach. In sum,adenosine release enhancement-whether by
adenosine uptake blockade, inhibition of adenosine metabolism, or
promotion of adenosine release (as may occur with the xanthine
oxidase inhibitor oxyputinal; Rudolphi et al., 1992)-would appear
to be a worthwhile investigational approach for anticonvulsant drug
development.
7.The Special Problem of Absence Epilepsy
Absence epilepsy, commonly referred to aspetit mal, is a child-
hood neurologicaI disorder characterized by episodes of sudden loss
of awareness lasting 3-10 s (Penry et aI., 1975). A child exhibiting
an absence attack becomes immobile, stares, and may display an
automatism such as eyelid fluttering or a slight movement of the face.
There is no loss of body tone (falling), as in generalized tonic-clonic
seizures. Absence seizures have a characteristic electroencephalo-
graphic signature consisting of bilateral, symmetrical, synchronous,
3 Hz spike-wave bursts. The disorder is rare (constitutingperhaps 8%
of patients with childhood epilepsy) and usually self-limiting
(absence seizures typically remit by adolescence). Absence seizures
are fundamentally different from other types of human epilepsies in
several respects. For the purposes of this discussion, the most impor-
tant difference is the unique pharmacologica1 responsiveness of
absence seizures. Ethosuxirnide, a drug with little activity in other
 seizure types, is highIy effective in the treatment of absence seizures.
Conversely, absence seizures are worsened by antiepif eptic drugs,
such as phenytoin and carbamazepine, that are effective in general-
ized convulsive and partial epilepsies, This pharmacologicalevidence
provides strong support for the concept that the pathophysiological
mechanisms underlying absence seizures are distinct from those of
generalized convulsive or partial epilepsies. Indeed, absence sei-
zures are beIieved to represent a disorder of corticothalarnic rhyth-
micity, as originalIy proposed in the corticoreticular hypothesis of
Gloor (1 968). Therefore, the brain systems meditating absence sei-
zures may be entirely distinct from those that participate in other
seizure types,
Current understanding of absence seizure mechanisms derives
frornextensive studies of Gloor and his colleagueswith the penicillin
model of generalized spike-and-wave in the cat (Gloor, E 984). These
studies were based on the historic work of Penfield and Jasper in the
1940s and 1950s (see Jasper, 199 1) on centrencephalicseizures (i.e.,
seizures that arise in both hemispheres simultaneously and are asso-
ciated with immediate Ioss of consciousness, as in absence seizures).
It was hypothesized by Penfield and Jasper that centrencephalic sei-
zuresare generated by activity in subcortical structures, including the
thalamus, with widespread projections to the cortex. This hypothesis
was refined by Gloot, who proposed that the cortex and thalamus
acted in concert during generalized seizures. Simultaneous record-
ings in the cortex and thalamus of cats treated with penicillin dem-
onstrated a pattern of firing during each burst consistent with the
circulation of impulse flow within a loop between thalamus and
cortex (Avoli et al., 1983; Avoli, 1 987). Tn agreement with this idea
was the observation that both cortex and thalamus ate required for
spike-and-wave discharges: surgical removal or pharmacological
inhibition of either eliminates epileptifom activity. The critical
involvement of cortex and thalamus has now been confirmed in a
brain slice preparation (Coulter and Lee, 1993) and in the genetic
absence epilepsy rat from Strasbourg (GAERS), a more realistic
model of human absence epilepsy than the penicillin model in the cat
(Marescaux et al., 199213).
Epilepsy 245

A more detailed understanding of the cellular events in genera-

tion of the spike-wave discharges by the thalamocortical circuit has
come from electrophysiological (voltage clamp) studies of thalamic
neurons and, more recently, from modeling of the membrane poten-
tial of these cells using parameters derived from voltage clamp
experiments (Wang et al., 1991;Huguenard and McCormick, 1 992).
Burst firing in thalamic neurons is dependent on a slow potential,
referred to as the "low-threshold spike" (LTS), mediated by T-type
voltage-dependent Ca2+channels (Jahnsen and LlinBs, 1984a,b;
Suzuki and Rogawski, 1989;CouIter et al., 1989a). Strong hyperpo-
larization is required to prime (de-inactivate) T-type Ca2+channels
that are normally inactivated at resting potential. Activation of the
LTS in thalamocortical relay neurons is, in turn, dependent on inhibi-
tory drive from thalamic reticular nucleus neurons (Huguenard and
Prince, 1992b$,These neurons have intrinsic pacemaker activity that
generates rhythmic sequences of oscillatory bursts (Bal and
McComick, 1993). Interestingly, this burst firing is also dependent
on a T-type Ca2' current, but with somewhat different properties from
that present in relay neurons (Huguenard and Prince, 1992b). Tha-
lamic reticularnucleus neurons are GABAergic. These neurons form
recurrent inhibitory connections among themselves, and also pro-
vide a powerfuI inhibitory input necessary to de-inactivate T-type
CaZ+channels of relay neurons. The prolonged inhibitory postsynap-
tic potential (IPSP) in relay neurons is probably mediated by GABAA
and GABAB receptors (Thornson, 1988; Soltesz et al., 1989). Pres-
ently, the role of GABABreceptors in regulating the normal firing
of relay neurons is poorly defined (McCormick, 1 992; von Krosigk
et al., 1993). However, during seizure activity (as can be induced
with GABAA receptor antagonists in thalamic slices), GABAB
receptors appear to play a critical role in synchronizing the firing
(von Krosigk et al., 1993).
7.1. T-Type Vo liage-Dependent Ca2+Channel Antagonists
The fundamental insights from elech-ophysiologicalstudies of
the thalamus have led to a mechanistic understanding of the selective
antiabsence drug ethosuximide and have also suggested strategies
 for the development of new medications for absence seizures. Thus,
Coulter et a!. (1989b) demonstrated that ethosuximide produces a
modest (up to 40%)reduction in amplitude of the T-type Ca2+cur-
rent in thalamic neurons (see also Kostyuk et al., 1992; Huguenard
and Prince, 1994). The ECso for this effect is 200 pI4 and there is
a roughly 2&35% reduction in Ca2+current at ethosuximide con-
centrations within the clinically relevant concentration range. Corn-
puter simulations of individual thalamic neurons have shown that
even smaller reductions in the T-type Ca2+current could result in a
diminution of the LTS (Lytton and Sejnowski, 1992). These results
support the hypothesis that ethosuximide's effects on the T-type
Ca2+current selectively alter the dynamics of slow bursting in tha-
lamic relay neurons that could lead to protection against absence
seizures. Additionally, however, ethosuximide probably also acts
on the T-type Ca" current in nucleus reticularis neurons to reduce
their burst firing (Huguenard and Prince, 1992a). The effect on
reticularis neurons would diminish the hyperpolarizing influence
that these cells generate in relay neurons and that is necessary for
their burst firing. The dual action of exthosuximide an nucleus
reticularis and relay neurons would act in concert to interrupt
thalamic bursting, and in turn thalarnocortical synchronization
during absence seizures.
In additionto ethosuximide, dimethadione (the active metab-
olite of the anti-absence drug trirnethadione) and methylphenyl-
succinimide (the active metabolite of another anti-absence drug
methsuxirnide) have been shown to cause a reduction in the
T-type Ca2+current in both thalamic relay-neurons and nucleus
reticularis neurons (Coulter et al., 1 990; Huguenard and Prince,
1992a). In contrast, valproate, an agent that is also highly effec-
tive in the treatment of absence seizures, has not been found to
affect T-type Ca2+currents in thalamic neurons at clinically rel-
evant concentrations. Nonetheless, the drug has been reported to
affect a similar current in a peripheral neuron (Kelly et al., 1 990).
Whether valproate's activity as an absence agent relates to
effects on Ca2+channels or to effects on another molecular target
is unknown.
Epilepsy

7.2. GABA, Receptor Antagonists

The critical role of GABAR receptors in the generation of
absence seizures has been demonstrated in several animal models by
the use of selective GABAs agonists and antagonists. Thus, the
GABAs agonist baclofen enhanced, and the GABAB antagonist CGP
35348 inhibited, absence-like seizures in y-hydroxybutyrate-treated
rats (Snead, 1992),the GAERS rat (Liu et al., 1992;Marcscaux et al.,
1992a), and the lethargic mouse (Hosford et al., 1992).Interestingly,
in the lethargic mouse there is evidence for a genetic defect resulting
in the overexpression of GABABreceptors. These animals show a
modest increase in GABAe receptor density as assessed with
radioligand binding and also exhibit evidence of enhanced GABAR
receptor functional activity in brain slice recordings (Hosford et al.,
1992). In the GAERS rat, however, no such alteration in GABAB
receptors was observed (Spreafico et:al., 19933.Thus, while absence-
like seizures can occur in animal models as a result of a variety of
underlying pathophysiological mechanisms, GABAe receptor
antagonists appear to be effective in all instances.
The precise site at which GABAAantagonists exert their anti-
absence activity has not been defined with certainty. However, elec-
trophysiological studies in thalamic slices have supported the
hypothesis that, during seizure activity, synaptic activationof GABAR
receptors generates the hyperpolarization necessary to de-inactivate
the T-type CaZ+current (vonKrosigk et al., 1993).Interruption ofthis
hyperpolarizing influence by antagonists would prevent the seizure
activity, but would not affect normal ongoing activity, which seems
Iess dependent on GABABreceptor activation. Although there is now
extensive experimental evidence supporting the potentiaI cIinicaZ
utility of GABABantagonists as anti-absence agents, this will need
to be confirmed in clinical trials, now in progress.
7.3.Potential Anti-A bsence Drugs
if Unknown Mecha~ism

There are a variety of compounds that have an anticonvulsant

profile in animal seizure models simiIar to that of exthosuximide,but
whose mechanism of action is unknown. One such compound is the
imidazopyridine AHR- 1 2245 (2-[4-chEorophenyl]-3H-imadam[4,5-
blpyidine-3-acetamid) (Johnson et al., 1991). Like ethosuxirnide,
AHR- 12245 is active orally againstpentylenetetmzal seizures inboth
mice and rats, but is ineffective in the maximal electroshock test.
However, AHR- E 2245 has a substantially greater therapeutic index
than ethosuxirnideand is therefore an interesting candidate for evalu-
ation in the treatment of generalized absence seizures.
As noted in Sections 2.1.4. and 2.2.6.,GABA-potentiating m u -
roactive steroids and IoreclezaEe have profiles of activity similar to
that of ethosuxirnide. Whether these compounds will prove useful in
the treatment of absence seizures remains unknown.

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