Opioid agonists comprise the backbone of analgesic therapy. There is an ever increasing need for the synthesis and pharmacological profiling of novel morphine-like substances that offer less side effects and superior analgesia over traditional opiates. Chemical transformations that alter the opioid receptor selectivity and efficacy may lead to useful drugs.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 6�-acylaminomorphinans. 6�-Morphinamine and 6�-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 6�-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.This work was supported by research grant from the National Institute on Drug Abuse (DA034106-01) to SM.Results have been published in European Journal of Medicinal Chemistry (in press).

Novel 6�-acylaminomorphinans with analgesic activity

247th National Meeting (2014)

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