effects, or both; and (2) by binding of the indirect agonists, which are drugs that inhibit
the hydrolysis of ACh by AChE, thus prolonging the action of available ACh.
The principal directly acting cholinergic agonists include methacholine, carbachol,
and betanechol—agents which, unlike acetylcholine, are used clinically.
Acetylcholine (4.1) has, of course, both nicotinic and muscarinic action. Because
it is very rapidly hydrolyzed by AChE and even by aqueous solution, it is not used
therapeutically.
Methacholine (4.6) is hydrolyzed somewhat more slowly than acetylcholine because
of steric hindrance of the ester by the α-methyl group. Its activity is mainly muscarinic,
but it is used infrequently.
Carbachol (4.7) is a very potent agent because it is not an ester but a carbamate, and
is hydrolyzed slowly. It is used in glaucoma to reduce intraocular pressure.
Bethanechol (4.8) also has a prolonged effect, and finds application in stimulation of
the gastrointestinal tract and urinary bladder (both muscarinic effects) to relieve post-
operative atony.
Other cholinergic agonists have no therapeutic use. Muscarine (4.3) is an alkaloid
of the mushroom Anumita muscaria; muscarone (4.9) is its semisynthetic analog.
Pilocarpine (2.2) is found in the leaves of a shrub and can be used to increase salivation
or sweating. Arecoline (4.10) is also an alkaloid, and occurs in the betel nut that is
used as a mild euphoriant in India and Southeast Asia. Finally, oxotremorine (4.11) is
a synthetic experimental agent that produces tremors and is helpful in the study of
antiparkinsonian drugs.
4.2.4.1 Cholinergic Agonists: Structural Modifications of Acetylcholine
Structural modifications of acetylcholine influence the ability of analogs to function as
cholinergic agonists. These modifications fall into four categories: (1) changes in the
quaternary ammonium group; (2) changes in the ethylene chain; (3) changes in the ester
group; and (4) the creation of cyclic analogs of the neurotransmitter.
210 MEDICINAL CHEMISTRY