A pharmacodynamic model to investigate the structure-activity profile of a series of novel opioid analgesics

MW Lutz, PH Morgan, MK James, PL Feldman, MF Brackeen, AP Lahey, SV James, JM Bilotta and JC Pressley

Glaxo Research Institute, Research Triangle Park, North Carolina.

A simple mathematical model of analgesia in the rat is developed and utilized to determine quantitative structure-activity relationships for a series of novel 4-anilidopiperidine opioids. The compounds tested (selected alkyl carboxyethyl esters attached at the one position of the piperidine ring) were designed for rapid inactivation by blood and tissue esterases. Model parameters included potency and rate constants for loss of pharmacodynamic effect by hydrolysis dependent and independent processes. A significant correlation is observed between duration of pharmacological effect in vivo and the rate constant for hydrolysis in human blood (r = 0.89). In vivo potency shows a moderate correlation with log P2 (r = -0.77). The validity of the model is shown by comparing model-based parameters which characterize potency and duration of effect in vivo with graphically derived parameters. Significant correlations are observed between model and graphically based estimates of potency (r = 0.75) and between model and graphically based estimates of duration of effect (r = 0.70). This model has potential application in studies of other classes of compounds in which hydrolytic cleavage limits duration of pharmacologic effect.

Volume 271, Issue 2, pp. 795-803, 11/01/1994
Copyright © 1994 by American Society for Pharmacology and Experimental Therapeutics