title: Only one pharmacophore is required for the kappa opioid antagonist selectivity of norbinaltorphimine.
abstract: We have investigated whether one or two pharmacophores are required for the kappa opioid receptor selectivity of the bivalent opioid antagonist norbinaltorphimine, (-)-1 (nor-BNI), by the synthesis and testing of its meso isomer 2. In smooth muscle preparations 2 was more potent than 1 and about half as selective as a kappa antagonist. Since 2 contains only one antagonist pharmacophore but yet retains substantial kappa selectivity, it is concluded that kappa selectivity is not dependent on the presence of two (-)-naltrexone-derived pharmacophores of 1. It is suggested that the kappa selectivity of (-)-1 and 2 is derived from the portions of the second halves of these molecules in that they mimic key "address" components of dynorphin at kappa opioid receptors.
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis 55455.
authors.forename: P S
authors.initials: PS
authors.lastname: Portoghese
authors.forename: H
authors.initials: H
authors.lastname: Nagase
authors.forename: A E
authors.initials: AE
authors.lastname: Takemori
mesh_terms: D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D003496:Cyclazocine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors; D016308:Enkephalin, Leucine-2-Alanine; D016314:Ethylketocyclazocine; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D009020:Morphine / Q000037:antagonists & inhibitors; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D011957:Receptors, Opioid / Q000187:drug effects* / Q000502:physiology; D017473:Receptors, Opioid, kappa; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology
chemical_list: D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; C051844:norbinaltorphimine; D016314:Ethylketocyclazocine; D004743:Enkephalin, Leucine; D009271:Naltrexone; D016308:Enkephalin, Leucine-2-Alanine; D009020:Morphine; D003496:Cyclazocine