title: Nonequilibrium opioid antagonist activity of 6,14-dideoxynaltrexone derivatives.
abstract: A series of 6,14-dideoxynaltrexones that contain different electrophiles in the 6-position were synthesized and evaluated for nonequilibrium opioid antagonist activity in the guinea pig ileum and mouse vas deferens preparations. Members 3-5 of the series possessed irreversible antagonist activity profiles similar to those previously reported for the 14-hydroxy analogues. In contrast, the 14-deoxy-beta-funaltrexamine (14-deoxy-beta-FNA) analogue (6) exhibited a profile of irreversible antagonist activity that differed from that of beta-FNA. It was concluded that the 14-hydroxy group is not essential for irreversible blockage when the electrophile is capable of reacting with a broad spectrum of nucleophiles. However, with a highly selective electrophile such as the fumarate group, the 14-hydroxy function appears to play a role in aligning the molecule to optimize attack by a receptor-based nucleophile.
mesh_terms: D000818:Animals; D003496:Cyclazocine / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D016308:Enkephalin, Leucine-2-Alanine; D016314:Ethylketocyclazocine; D006168:Guinea Pigs; D051379:Mice; D009271:Naltrexone / Q000031:analogs & derivatives*; D009292:Narcotic Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D011957:Receptors, Opioid / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D009292:Narcotic Antagonists; D011957:Receptors, Opioid; D016314:Ethylketocyclazocine; D004743:Enkephalin, Leucine; D009271:Naltrexone; D016308:Enkephalin, Leucine-2-Alanine; D003496:Cyclazocine