Design, Synthesis, and Pharmacological Evaluation of Ultrashort- to Long-Acting Opioid Analgetics

Article abstract of DOI:10.1021/jm00111a041

In an effort to discover a potent ultrashort-acting μ opioid analgetic that is capable of metabolizing to an inactive species independent of hepatic function, several classes of 4-anilidopiperidine analgetics were synthesized and evaluated.One series of compounds displayed potent μ opioid agonist activity with a high degree of analgesic efficacy and an ultrashort to long duration of action.These analgetics, 4-(methoxycarbonyl)-4-<(1-oxopropyl)phenylamino>-1-piperidinepropanoic acid alkyl esters, were evaluated in vitro in the guinea pig ileum for μ opioid activity, in vivo in the rat tail withdrawal assay for analgesic efficacy and duration of action, and in vitro in human whole blood for their ability to be metabolized in blood.Compounds in this series were all shown to be potent μ agonists in vitro, but depending upon the alkyl ester substitution the potency and duration of action in vivo varied substantially.The discrepancies between the in vitro and in vivo activities and variations in duration of action are probably due to different rates of ester hydrolysis by blood esterase(s).The SAR with respect to analgesic activity and duration of action as a function of the various esters synthesized id discussed.It was also demonstrated that the duration of action for the ultrashort-acting analgetic, 8, does not change upon prolonged infusion or administration of multiple bolus injections.