title: Novel 'soft' anticholinergic agents.
abstract: The concepts involved in the design of 'soft' drugs (drugs which, after achieving their therapeutic role, are metabolised in a predictable manner and at a controlled rate to non-toxic moieties) have been further applied in the case of atropine. Selected aliphatic and cycloaliphatic esters of a hypothetical, inactive acidic metabolite of atropine were designed and found to have atropine-like activity, and to revert to the inactive metabolite in rat liver homogenates. Peak anticholinergic activity, measured by the degree of antagonism of carbachol-induced spasms of guinea pig ileum strips, was observed when the esters contained a quaternary group. The in vitro stability of the esters was determined in human plasma, in pH 12 buffer solution, and in rat liver homogenate; the fastest rate of hydrolysis occurred in rat liver homogenate, and least sterically hindered esters degraded more rapidly than hindered esters. Synthesis of the esters was achieved in two stages. Phenylmalonic acid and the appropriate alcohol gave phenylmalonic acid monoesters, which, after reaction with tropine, afforded the required diesters. The tertiary amine group on the tropine moiety of the diesters then allowed the preparation of quaternary derivatives.
authors.affiliation: College of Pharmacy, J. Hillis Miller Health Center, University of Florida, Gainesville 32610-0497.
authors.forename: R H
authors.initials: RH
authors.lastname: Hammer
authors.forename: K
authors.initials: K
authors.lastname: Amin
authors.forename: Z E
authors.initials: ZE
authors.lastname: Gunes
authors.forename: G
authors.initials: G
authors.lastname: Brouillette
authors.forename: N
authors.initials: N
authors.lastname: Bodor
mesh_terms: D000818:Animals; D001286:Atropine Derivatives / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D001673:Biodegradation, Environmental; D015195:Drug Design; D006168:Guinea Pigs; D006801:Humans; D006868:Hydrolysis; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D008099:Liver / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D010276:Parasympatholytics / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D001286:Atropine Derivatives; D007202:Indicators and Reagents; D010276:Parasympatholytics