Soft drugs. 13: Design and evaluation of phenylsuccinic analogs of scopolamine as soft anticholinergics.
Concepts involved in the design of soft drugs (drugs which, after achieving their therapeutic role, are metabolized in a predictable manner and at a controlled rate to non-toxic moieties) have been applied to methscopolamine. Selected aliphatic and cycloaliphatic esters (4a-e) of a hypothetical metabolite (2a) of methscopolamine with a phenylsuccinic acid basic structural moiety were designed and found to have anticholinergic activity and to revert to the original hypothetical metabolite in biological media with fairly short half lives. The pA2 values of the soft drugs were determined and the hypothetical metabolite was found 100 times less potent than the most potent compound (4a) of the series. The anticholinergic activities were found to be dependent on the length of the side chain alcohol.
Department of Medicinal Chemistry, JHMHC, University of Florida 32610.
G N
GN
Kumar
R H
RH
Hammer
N S
NS
Bodor
D000818:Animals; D015195:Drug Design; D004341:Drug Evaluation; D004355:Drug Stability; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D010276:Parasympatholytics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D012602:Scopolamine Derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D010276:Parasympatholytics; D012602:Scopolamine Derivatives