current

time

Drugs and the Brain

Channel blockers 1
Pore Blockers at ligand
ligand-gated
gated channels
2013 California Institute of Technology

Single-channel traces & Atomic-Scale Structure: Local Anesthetic in an Ion Channel

Muscle nicotinic receptor

No drug

Bacterial pentameric ligand-gated

ligand gated channel

+q
quaternary
y lidocaine
derivative 20 M
3 pA
12 ms

current
ti
time

Charnet et al.,
Neuron 1990

Brominated
lidocaine
derivative
(only the Br
was resolved).

Hilf et al., Nature Struct. Mol. Biol. 2010

PDB 2XQ3

Mecamylamine,
clinicallyy used channel blocker,,
peripheral nicotinic receptors.
Indication: hypertension

Failed as a central nervous system drug for depression

AMPA receptor antagonists have primarily been useful for research . . .

But perampanel was recently approved for epilepsy

Hibi, J Med Chem, 2012

Memantine, an NMDA channel blocker approved for Alzheimers disease

Probably blocks extrasynaptic NMDA receptors

Zigmond et al. (Eds.)

Fundamental Neuroscience,
Sinauer (1999)

currentt
time

Drugs and the Brain

End of miniLecture
Channel blockers 1

2013 California Institute of Technology

Drugs and the Brain

Channel blockers 2
Voltage-gated
Voltage
gated channel blockers
2013 California Institute of Technology

The membrane potential controlled by ligand-gated and voltage-gated channels

Resting

GK

Voltage-gated

Ligand-gated

outside
GEPSP

GCl

GK

GNa

Capacitance
EK
-90 mV

EEPSP
~ -5 mV

cytosol = inside

ECl
-80 mV

EK
-90 mV

ENa
+50 mV

+60

mV

-60

resting
potential:
K+ channels

ms

Excitatory Inhibitory postsynaptic

postsynaptic
responses:
responses
Cl- channels

peak of action
potential:
Na+ channels

E K GK E EPSP GEPSP E Cl GCl E NaGNa

V
GK G EPSP G Cl G Na

afterhyperpolarization:
more K+ channels
open
p

More resources on voltage-gated channels and action potentials:

See the Duke University / Coursera offering, Bioelectricity

Voltage-gated Na+ channels, and Blockade by Tetrodotoxin

The pufferfish toxin,
toxin
from PubChem

Payandeh et al,
al
Nature 2011;
Zhang et al,
Nature 2012;

Animal Na+ channels have

an inactivation flap
PDB files: 4EKW, 4DXW

Most Na+ Channel Blockers in Clinical Use Act from Inside the Cell

inside
Functioning
channel

Trapped or
Use-Dependent
Blocker

procaine-H+

procaine-H+
procaine
p

current

no current

inside
Functioning
channel

Functioning channel

Trapped
Trapped or
Use-Dependent
Blocker

Drug-blocked channel

Procainamide, a use-dependent blocker

stimuli

Action potentials fail

threshold

voltage)

Na+
channels
pronounced block
at brief intervals

little block
at long intervals

Na+ channel blockers in medicine

Local anesthetics
Dental surgery (lidocaine)
Sunburn medications
Antiarrhythmics (heart)
use-dependent blocker
example:
p (p
(procainamide))
Antiepileptics / anticonvulsants (brain)
use-dependent blocker
(phenytoin)

Unwanted Ion Channel Blockade

Many candidate neural drugs block the
cardiac K+ channel called hERG (human
ether-a-go-go related gene). The binding site
lies in a water
water-filled
filled cavity.
This lengthens the cardiac action potential so
much that it interferes with the next action
potential,
causing
potentially
fatal
arrhythmias.

Ion selectivity
filter

Na+ channels open

K+ channels open
~ 100 mV

Gate

~ 1 sec

Experts estimate that ~40%

candidates cause hERG blockade.
Bacterial
B
i l
K+ channel

Doyle
D
l ett al,l
Science, 1998

of

drug

The FDA now requires

q
that all new drugs
g
pass a hERG safety test.

Drugs and the Brain

End of miniLecture
Channel blockers 2
2013 California Institute of Technology