Pilocarpine and Analogs and Congeners

Pilocarpine (128), the chief alkaloid from the leaflets of shrubs of the genus Pilocarpus, has a dominant muscarinic action, but it causes

anomalous cardiovascular responses, and the sweat glands are particularly sensitive to the drug (165).

Its structure is distinguished by the lack of a quaternary ammonium head; however it is presumed that a nitrogen-protonated cation is the biologically active species. Pilocarpine has been described as a muscarinic partial agonist

(166). Structural and conformational analogies and interatomic distance similarities between pilocarpine and muscarinic agonists such as acetylcholine, acetyl j3-methylcholine, muscarine, and muscarone have been invoked

(167) to rationalize pilocarpine's pharmacologic properties. The potential utility of pilocarpine in treatment of glaucoma is limited by its low ocular bioavailability. A double prodrug strategy (168, 169) involves hydrolytic cleavage of the lactone ring of pilocarpine and esterification of the freed carboxyl and alcohol groups (129) to produce derivatives with a greatly enhanced lipophilic character. In the presence of human plasma or rabbit eye ho-mogenates, pilocarpine was reformed from these derivatives in quantitative amounts because of the action of tissue esterases.

Cyclic carbamate analogs (130-132) of pilocarpine were designed (170) to extend pilocarpine's duration of action, which is a reflection of its metabolic inactivation by hydrolytic cleavage of the lactone ring.

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