Aromatic esters of nonquaternary carbon-4 piperidinols as analgesics.
Aromatic carboxylic esters of 1-methyl-4-piperidinol were prepared and evaluated for analgesic activity. In addition, aralkyl, alkyl, and cycloalkyl carboxylates of the 4-piperidinol system and 3,4-dimethoxybenzoates of isomeric piperidinols (24-26) were synthesized. The 3,4-dimethoxybenzoate 23 was nearly twice as active as codeine in the mouse hot-plate assay. In monkeys, 23 showed no morphine-like physical dependence liability, cis- and trans-1,3-dimethyl-4-piperidinol esters 24 and 25 showed no binding to the opiate receptor in rat brain homogenates. The 3- and 4-monosubstituted and the 3,4-disubstituted benzoate esters were examined for qualitative structure-activity relationships with respect to parameters Esc and pi. Various structural features of this series of compounds that may have an affinity for receptor binding sites are discussed.
D000698:Analgesia; D000700:Analgesics / Q000138:chemical synthesis* / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000648:ultrastructure; D003061:Codeine / Q000494:pharmacology; D004952:Esters; D000882:Haplorhini; D066298:In Vitro Techniques; D051379:Mice; D010880:Piperidines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011930:Reaction Time / Q000187:drug effects; D011957:Receptors, Opioid / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship
D000700:Analgesics; D004952:Esters; D010880:Piperidines; D011957:Receptors, Opioid; D003061:Codeine