Soft drugs--XVI. Design, evaluation and transdermal penetration of novel soft anticholinergics based on methatropine.
Atropine has been reported to produce unwanted systemic side effects on topical administration into the eye. The same problem could arise when atropine is used topically as a suppressant of eccrine sweating. In this study, the principles of soft drug design were applied to methatropine. A hypothetical carboxylate metabolite of methatropine was reactivated by esterification with cyclic and alicyclic alcohols to yield a series of compounds (3a-g). In vitro evaluation by guinea pig ileum assay indicated that the compounds are potent anticholinergics and the lead carboxylate metabolite is about 60 times less potent than the most active compound of the series. The activity was found to decrease with the increasing side chain length. The n-octanol/water partition coefficients were found to be directly dependent on the chain length for the compounds made with straight chain alcohols. The transdermal permeability coefficients across the hairless mice skin were found to be directly dependent on the partition coefficients. The soft drugs are found to metabolize extensively during the penetration process compared to the unmetabolizable nature of methatropine. The soft drugs reported in this study will probably be able to elicit a local action at the site of application but will probably be metabolized rapidly in the systemic circulation, thereby avoiding the systemic side effects with a consequent increase in the therapeutic index.
Kumar
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GN
Center for Drug Discovery, JHMHC, College of Pharmacy, University of Florida, 32610.
Hammer
R H
RH
Bodor
N S
NS
D000279:Administration, Cutaneous; D000818:Animals; D001286:Atropine Derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008812:Mice, Hairless; D015394:Molecular Structure; D010276:Parasympatholytics / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D012867:Skin / Q000378:metabolism; D013329:Structure-Activity Relationship
D001286:Atropine Derivatives; D010276:Parasympatholytics; C006649:methylatropine