Novel 6beta-acylaminomorphinans with analgesic activity.

Abstract

Aminomorphinans are a relatively young class of opioid drugs among which substances of high in vitro efficacy and favorable in vivo action are found. We report the synthesis and pharmacological evaluation of novel 6beta-acylaminomorphinans. 6beta-Morphinamine and 6beta-codeinamine were stereoselectively synthesized by Mitsunobu reaction. The aminomorphinans were subsequently acylated with diversely substituted cinnamic acids. In vitro binding studies on cinnamoyl morphinamines showed moderate affinity for all opiate receptors with some selectivity for mu opioid receptors, while cinnamoyl codeinamines only showed affinity for mu opioid receptors. In vivo analgesia studies showed significant analgesic activity of 6beta-cinnamoylmorphinamine mediated by mu and delta receptors. The lead compound was found to be roughly equipotent to morphine (ED50 3.13 +/- 1.09 mg/kg) but devoid of the dangerous side-effect respiratory depression, a major issue associated with traditional opioid therapy.