Article ID Journal Published Year Pages File Type
1399059 European Journal of Medicinal Chemistry 2013 4 Pages PDF
Abstract

•We designed and synthesized the 6β-acylamino derivatives of morphine and codeine.•The synthesis of 10 novel potentially analgesic compounds is reported.•The compounds were tested for opioid receptor binding and in vivo analgesia.•6β-Cinnamoylmorphinamine were shown to possess MOR-1/DOR-1 analgesia.•6β-Cinnamoylmorphinamine did not cause respiratory depression.

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 6β-acylaminomorphinans. 6β-Morphinamine and 6β-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 6β-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.

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Physical Sciences and Engineering Chemistry Organic Chemistry
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