Medicinal Chemistry

4.7.3 GABA Receptors: Presynaptic Drug Effects

Presynaptic drug effects can interfere with the metabolism, storage, release, and reuptake
of GABA, as they can with the functioning of other neurotransmitters.

4.7.3.1 GABA Synthesis Inhibitors

GABA synthesis inhibitors act on the enzymes involved in the decarboxylation and
transamination of GABA. Glutamic acid decarboxylase (GAD), the first enzyme in
GABA biosynthesis, is inhibited easily by carbonyl reagents such as hydrazines [e.g.,
hydrazinopropionic acid (4.164) or isonicotinic acid hydrazide (4.165)], which trap
pyridoxal, the essential cofactor of the enzyme. A more specific inhibitor is allylglycine
(4.166). All of these compounds cause seizures and convulsions because they decrease
the concentration of GABA.

4.7.3.2 GABA Metabolism Inhibitors

In contrast to GABA synthesis inhibitors, inhibitors of GABA-T, the transaminase
active in eliminating GABA, increase the concentration of this neurotransmitter. The
most potent of these agents are gabaculine (4.167) and vigabatrin (4.168), both of
which protect against drug-induced seizures.

4.7.3.3 GABA Reuptake Inhibitors

Another mechanism involves several GABA reuptake inhibitors, such as nipecotic acid
(4.169) and other related compounds such as tiagabine (4.170). Mechanistically, these
may be thought of as glial GABA uptake blockers. By this mechanism, they block
uptake of GABA into adjacent glial cells and thus block GABA breakdown.

4.7.3.4 Agents Affecting GABA Release

High doses of imipramine, haloperidol, and chlorpromazine (at 1 μM concentrations) are
known to inhibit GABA release in vitro. Baclofen, [β-(p-chlorophenyl)-GABA] (4.171), is
a valuable compound which enhances GABA release and is therefore an indirect agonist.

272 MEDICINAL CHEMISTRY