Synthesis and Biological Evaluation of Alpha- and Beta-6-Amido Derivatives of 17-Cyclopropylmethyl-3, 14 Beta-Dihydroxy-4, 5 Alpha-Epoxymorphinan: Potential Alcohol-Cessation Agents


Substituted aryl and aliphatic amide analogues of 6-naltrexamine were synthesized and used to characterize the binding to and functional activity of human μ-, δ-, and κ-opioid receptors. Competition binding assays showed 1125 and 2731 bound to the μ (Ki = 0.05–1.2 nM) and κ (Ki = 0.06–2.4 nM) opioid receptors. Compounds 1118 possessed significant binding affinity for the δ receptor (Ki = 0.8–12.4 nM). Functional assays showed several compounds acted as partial or full agonists of δ or κ receptors while retaining an antagonist profile at the μ receptor. Structure–activity relationship for aryl amides showed that potent compounds possessed lipophilic groups or substituents capable of hydrogen bonding. Metabolic stability studies showed that 1112, and 14 possessed considerable stability in the presence of rat, mouse, or human liver preparations. The ED50 of inhibition of 10% ethanol self-administration in trained rats, using operant techniques for 11, was 0.5 mg/kg.[…]

Read more from SRI