Further structure-activity relationships in the series of tropanyl esters endowed with potent antinociceptive activity

Several analogs of the alpha-tropanyl esters of 2-(4-chlorophenoxy)butyric acid (SM21) and 2-phenylthiobutyric acid (SM32), endowed with potent antino ciceptive and cognition enhancing activity, were synthesized, aimed at obta ining more potent and safe drug candidates. Variation of the acyl moiety (4 -11), as well as the conformational restriction of atropine to give the a-t ropanyl ester of 2,3-dihydrobenzofurane-3-carboxylic acid (18), practically abolished activity. In the case of 18, the antimuscarinic activity was als o severely affected by the conformation restrain. On the contrary, conforma tional restriction of phenoxybutyric and phenylthiobutyric acid derivatives to give the alpha-tropanyl ester of 2,3-dihydro-benzofurane-2-carboxylic a cid and 2,3-dihydro-benzothiophene-2-carboxylic acid (12-17), afforded pote nt analgesic drugs that unfortunately were too toxic to be reliable drug ca ndidates. A series of related esters of benzofurane-3-carboxylic acid (20-2 7) and benzothiophene-3-carboxylic acid (28) were also studied and found to be potent but toxic analgesics. (C) 1998 Elsevier Science S.A. All rights reserved.