Quantitative structure-activity relationships of aromatic esters of 1-methyl-4-piperidinol as analgesics.
Substituted benzoic acid esters of 1-methyl-4-piperidinol showed analgesic activity when assayed by the mouse hot-plate methods, the more potent ones falling in the morphine-codeine range. To understand how substituents on the aromatic ring affect the analgesic potency, quantitative structure-activity correlations were carried out on a series of 44 derivatives. Among the various substituent parameters included in the study, Lortho (Length of ortho-substituents) and B1 (minimal width of substituents) or E8 at meta and para positions gave negative correlation with the potency, while lipophilicity (especially pi meta) and the ability of being a hydrogen-bond acceptor enhanced the potency. Based on the QSAR results, a substitution pattern of the phenyl group was defined for optimal activity. Implications on drug-receptor interactions and the possible binding mode of these compounds were discussed.
D000700:Analgesics / Q000138:chemical synthesis*; D000818:Animals; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006860:Hydrogen Bonding; D008614:Meperidine / Q000494:pharmacology; D051379:Mice; D008968:Molecular Conformation; D009020:Morphine / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology; D011930:Reaction Time / Q000187:drug effects; D013329:Structure-Activity Relationship
D000700:Analgesics; D010880:Piperidines; D009020:Morphine; D008614:Meperidine