Soft drugs--XIV. Synthesis and anticholinergic activity of soft phenylsuccinic analogs of methatropine.
Three soft drug analogs and a metabolite of methatropine based on phenylsuccinic structural moiety were synthesized and tested for activity. In an in vivo assay, the soft drugs were found to be two orders of magnitude less potent than methatropine while the carboxylate metabolite was found to be one order of magnitude less potent than the soft drugs. A structural isomer of compound 4a was found to be less potent. All the soft drugs tested elicited shorter durations of mydriatic action in rabbit eyes compared to atropine. The untreated eye was dilated in the atropine treated animals while no dilation occurred in the soft drug treated animals indicating facile systemic metabolism of the soft drugs to inactive moieties, possibly the carboxylate metabolite. In in vitro stability studies, the soft drugs have been found to be more hydrolytically labile than atropine. The shorter duration of mydriatic action of compound 4a coupled with increased hydrolytic lability make this a candidate for further study.
Hammer
R H
RH
Center for Drug Discovery, College of Pharmacy, University of Florida, Gainesville 32610.
Gunes
E
E
Kumar
G N
GN
Wu
W M
WM
Srinivasan
V
V
Bodor
N S
NS
D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001286:Atropine Derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004355:Drug Stability; D006801:Humans; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D015394:Molecular Structure; D009184:Mydriatics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010276:Parasympatholytics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011680:Pupil / Q000187:drug effects; D011817:Rabbits; D051381:Rats; D013329:Structure-Activity Relationship
D001286:Atropine Derivatives; D009184:Mydriatics; D010276:Parasympatholytics; D001285:Atropine; C006649:methylatropine