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Agonists—Antagonists

An agonist (A) has affinity (tendency to adhere) for a receptor and affects the receptor

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protein in such a manner as to cause a change in cell function—“intrinsic activity.”

The biological effect of the agonist (i. e., the change in cell function) depends on the
effectiveness of signal transduction steps associated with receptor activation. The
maximal effect of an agonist may already occur when only a fraction of the available
receptors is occupied (B, agonist A). Another agonist (agonist B), possessing equal
affinity but less ability to activate the receptor and the associated signal transduction
steps (i. e., less intrinsic activity), will produce a smaller maximal effect even if all
receptors are occupied—smaller efficacy. Agonist B is a partial agonist. The potency of
an agonist is characterized by the concentration (EC50) at which a half-maximal effect is
attained.

Antagonists (A) attenuate the effect of agonists: they act “antiagonistically.”

Competitive antagonists possess affinity for the receptors, but their binding does not
elicit a change in cell function. In other words, they are devoid of intrinsic activity. When
present simultaneously, an agonist and competitive antagonists vie for occupancy of
the receptor. The affinities and concentrations of both competitors determine whether
binding of agonist or antagonist predominates. By increasing the concentration of
the agonist, blockade induced by an antagonist can be surmounted (C): that is, the
concentration– effect curve of the agonist is shifted “right”—to higher concentrations—
with preservation of the maximal effect.

Models of the Molecular Mechanism of Agonist/Antagonist Action (A)

Agonist induces an active conformation.

The agonist binds to the inactive receptor and thereby causes the resting conformation
to change into the active state. The antagonist attaches to the inactive receptor without
altering its conformation.

Agonist stabilizes spontaneously occurring active conformation. The receptor may

spontaneously “flip” into the active conformation. Usually, however, the statistical
probability of such an event is so small that a spontaneous excitation of the cells
remains undetectable. Selective binding of the agonist can occur only to the active
conformation and thus favors the existence of this state. The antagonist shows affinity
only for the inactive state, promoting existence of the latter. If the system has little
spontaneous activity, no measurable effect will result from adding an antagonist.
However, if the system displays high spontaneous activity, the antagonist is liable to
produce an effect opposite to that of an agonist: inverse agonist. A “true” antagonist
without intrinsic activity (“neutral antagonist”) displays equal affinity for the active and
inactive conformations of the receptor and does not interfere with the basal activity of
the cell. According to this model, a partial agonist has less selectivity for the active state;
however, to a certain extent it binds also to the inactive state.

Other Forms of Antagonism

Allosteric antagonism. The antagonist is bound outside the agonist’s site of attachment at

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the receptor and induces a decrease in agonist affinity. The latter is increased in the case
of allosteric synergism.

Functional antagonism. Two agonists acting via different receptors affect the same
variable (e. g., luminal diameter of bronchi) in opposite directions (epinephrine† dilation;
histamine † constriction). 60 Drug–Receptor Interactions.

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