Quantitative structure-activity relationships of aromatic esters of 1-methyl-4-piperidinol as analgesics.

ABSTRACT

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.