Drug-Receptor Interaction V

Enantioselectivity of affinity. If a
receptor has sites for three of the substituents
(symbolized in B by a cone, a
sphere, and a cube) on the asymmetric
carbon to attach to, only one of the
enantiomers will have optimal fit. Its affinity
will then be higher. Thus, dexetimide
displays an affinity at the muscarinic
ACh receptors almost 10000 times
that of levetimide; and at !-
adrenoceptors, S(-)-propranolol has an
affinity 100 times that of the R(+)-form.
Enantioselectivity of intrinsic activity.
The mode of attachment at the
receptor also determines whether an effect
is elicited and whether or not a substance
has intrinsic activity, i.e., acts as
an agonist or antagonist. For instance,
(-) dobutamine is an agonist at "-adrenoceptors
whereas the (+)-enantiomer is
an antagonist.
Inverse enantioselectivity at another
receptor. An enantiomer may
possess an unfavorable configuration at
one receptor that may, however, be optimal
for interaction with another receptor.
In the case of dobutamine, the
(+)-enantiomer has affinity at !-adrenoceptors
10 times higher than that of the
(-)-enantiomer, both having agonist activity.
However, the "-adrenoceptor
stimulant action is due to the (-)-form
(see above).
As described for receptor interactions,
enantioselectivity may also be
manifested in drug interactions with
enzymes and transport proteins. Enantiomers
may display different affinities
and reaction velocities.
Conclusion: The enantiomers of a
racemate can differ sufficiently in their
pharmacodynamic and pharmacokinetic
properties to constitute two distinct
drugs.