172 Heterocycles in Medicine
Anticholinesterase agents
The physiological activity of acetylcholine relies on local release, stimulation of the receptor then rapid hydrolysis by acetyl-
cholinesterase, which results in deactivation. The indole alkaloid physostigmine, from the West African Calabar bean, and
the relatively simple synthetic compound pyridostigmine, which has a more obvious relationship to choline, are reversible
inhibitors of acetylcholinesterase. Controlled inhibition of the enzyme by such drugs, which results in a build-up of ACh, is
useful in conditions such as myasthenia gravis, a muscle weakness that is caused by insuffi cient production of ACh.
Irreversible inhibition of acetylcholinesterase is the mechanism of action of poisoning by nerve gases such as Sarin
and to a lesser degree by other organophosphates such as those used as insecticides, leading to persistent and wide-
spread excessive cholinergic effects. The inhibition is due to phosphorylation of a serine hydroxyl group at the active
site of the enzyme – this OH is the nucleophile that attacks the acetyl group during physiological functioning of the
enzyme. It is possible to reactivate the enzyme, provided treatment is given promptly, by use of pralidoxime. Here,
theN-methylpyridinium binds via electrostatic forces to the same site as the choline trimethylammonium grouping,
bringing the very nucleophilic oxime oxygen close enough to attack the phosphoryl group, releasing the serine OH.
Atropine would also be given concurrently to antagonise the effects of the excess ACh.
5-Hydroxytryptamine (5-HT) (serotonin)
5-Hydroxytryptamine has at least 14 receptors and sub-types. Compounds acting on these receptors are drugs for the treat-
ment of cardiovascular, gastrointestinal and central nervous systems. Sumatriptan, a 5-HT1D agonist acts, at least in part,
by causing vasoconstriction selectively in intracranial blood vessels, opposing the vasodilation that is a component of the
pathological basis of migraine. The discovery of the triptan class of drugs was a major advance in the treatment of migraine.
The 5-HT 3 antagonists ondansetron and granisetron are effective in relieving the nausea and vomiting that are side-
effects of radiotherapy and treatment with cytotoxic drugs. They probably function by a combination of central and
peripheral actions.