Medicinal Chemistry

parasympathetic terminals involved in gastrointestinal and ureteral peristalsis, glandular
secretion, pupillary constriction, peripheral vasodilation, and heart rate reduction.
Acetylcholine is normally an excitatory neurotransmitter, although it can occasionally
show an inhibitory action in cardiac muscle. There, hyperpolarization rather than depo-
larization occurs because only K+can cross the muscle membrane. In the CNS, cholin-
ergic inhibition is seen in the thalamus and brainstem.

4.2.1 Acetylcholine Metabolism

Acetylcholine is synthesized by the reaction

Choline+Acetyl-CoA→Acetylcholine+CoA—SH

which is catalyzed by choline acetyltransferase. Acetyl-coenzyme A (CoA) is ubiqui-
tous; choline is obtained from phosphatidy1choline (lecithin) and free choline. Some of
this choline is recycled after ACh is hydrolyzed by acetylcholine esterase (AChE), ter-
minating the neuronal impulse (see chapter 8). There is a high-affinity transport system
(Km=1–5 M) for choline reuptake in the nerve endings, which can be inhibited by
hemicholinium (4.4). Unlike most other neurotransmitters, ACh itself is not taken up by
active transport into synapses.

As ACh is synthesized, it is stored in the neuron or ganglion in at least three differ-
ent locations. Eighty-five percent of all ACh is stored in a depot and can be released by
neuronal stimulation; it is always the newly synthesized neurotransmitter that is
released preferentially. The surplus ACh can be released by K+depolarization only.
Finally, there is stationary ACh, which cannot be released at all. It has been assumed
that the neurotransmitter in cholinergic and some other neurons is released through the
exocytosis of small transmitter-filled synaptic vesicles.
Acetylcholine release is inhibited by one of the most potent toxins, the botulinus toxin
produced by the anaerobic bacterium Clostridium botulinum. The toxin, lethal at 1 ng/kg
in humans, enters the synapse by endocytosis at nonmyelinated synaptic membranes and
produces muscle paralysis by blocking the active zone of the presynaptic membrane

206 MEDICINAL CHEMISTRY