Drug-Receptor Interaction III

Agonist stabilizes spontaneously
occurring active conformation. The
receptor can spontaneously “flip” into
the active conformation. However, the
statistical probability of this event is
usually so small that the cells do not reveal
signs of spontaneous receptor activation.
Selective binding of the agonist
requires the receptor to be in the active
conformation, thus promoting its existence.
The “antagonist” displays affinity
only for the inactive state and stabilizes
the latter. When the system shows minimal
spontaneous activity, application
of an antagonist will not produce a measurable
effect. When the system has
high spontaneous activity, the antagonist
may cause an effect that is the opposite
of that of the agonist: inverse agonist.
A “true” antagonist lacking intrinsic
activity (“neutral antagonist”) displays
equal affinity for both the active and inactive
states of the receptor and does
not alter basal activity of the cell.
According to this model, a partial agonist
shows lower selectivity for the active
state and, to some extent, also binds
to the receptor in its inactive state.
Other Forms of Antagonism
Allosteric antagonism. The antagonist
is bound outside the receptor agonist
binding site proper and induces a decrease
in affinity of the agonist. It is also
possible that the allosteric deformation
of the receptor increases affinity for an
agonist, resulting in an allosteric synergism.
Functional antagonism. Two agonists
affect the same parameter (e.g.,
bronchial diameter) via different receptors
in the opposite direction (epinephrine
dilation; histamine ! constriction).