title: Synthesis and kappa-opioid antagonist selectivity of a norbinaltorphimine congener. Identification of the address moiety required for kappa-antagonist activity.
abstract: Compound 2, which represents a structurally simplified congener of norbinaltorphimine 1a, was synthesized in order to evaluate the role of its second basic nitrogen in conferring kappa-opioid receptor antagonist selectivity. Congener 2 was found to be at least twice as selective as 1a as a kappa antagonist, while its N-carbobenzoxy derivative (3) was inactive at kappa-receptors. This study establishes the importance of the second basic nitrogen of 1a for kappa-receptor recognition. It is proposed that this basic group mimics the guanidinium moiety of Arg7, which may be the key kappa-address component of dynorphin.
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, Medical School, University of Minnesota, Minneapolis 55455.
authors.forename: C E
authors.initials: CE
authors.lastname: Lin
authors.forename: A E
authors.initials: AE
authors.lastname: Takemori
authors.forename: P S
authors.initials: PS
authors.lastname: Portoghese
mesh_terms: D000818:Animals; D004558:Electric Stimulation; D006168:Guinea Pigs; D051379:Mice; D009132:Muscles / Q000187:drug effects*; D009271:Naltrexone / Q000031:analogs & derivatives*; D009292:Narcotic Antagonists / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D009292:Narcotic Antagonists; C051844:norbinaltorphimine; D009271:Naltrexone