title: Pharmacologic profile of NPC 168 (naltrexone phenyl oxime), a novel compound with activity at opioid receptors.
abstract: NPC 168 (naltrexone phenyl oxime) was synthesized as a novel opioid antagonist and evaluated in several in vitro and in vivo assays. NPC 168 inhibited binding to the mu, delta and kappa subtypes of the opioid receptor with nanomolar potencies. The potency of NPC 168 to antagonize morphine-induced analgesia was slightly less than that of naltrexone and nalmefene following either intraperitoneal (ED50 = 0.07 mg/kg) or oral (ED50 = 0.82 mg/kg) administration. The duration of action of NPC 168 was approximately 8 hr following subcutaneous administration, compared to 4 hr for nalmefene, to antagonize oxymorphonazine-induced analgesia. The long duration of action of NPC 168 was substantiated by pharmacokinetic data that demonstrated rapid uptake and slow clearance of NPC 168 from brain. NPC 168 (5, 10 and 20 mg/kg) also inhibited cumulative 6-hr food intake in rats that were deprived of food for 24 hr, but chronic administration of this compound to rats over a three-week period resulted in a marginal reduction in cumulative body weight gain. NPC 168 at doses of up to 10 mg/kg did not produce a conditioned taste aversion. However, NPC 168 was slightly more toxic than either naltrexone or nalmefene when administered parenterally, and as toxic as nalmefene when administered by the oral route. These data demonstrate that NPC 168 is a novel opioid antagonist with a longer duration of action than either naltrexone or nalmefene.
authors.affiliation: Nova Pharmaceutical Corporation, Baltimore, MD 21224-2788.
authors.forename: D L
authors.initials: DL
authors.lastname: DeHaven-Hudkins
authors.forename: P A
authors.initials: PA
authors.lastname: Brostrom
authors.forename: J T
authors.initials: JT
authors.lastname: Allen
authors.forename: L J
authors.initials: LJ
authors.lastname: Lesko
authors.forename: J W
authors.initials: JW
authors.lastname: Ferkany
authors.forename: P V
authors.initials: PV
authors.lastname: Kaplita
authors.forename: B J
authors.initials: BJ
authors.lastname: Mavunkel
authors.forename: W J
authors.initials: WJ
authors.lastname: Rzeszotarski
authors.forename: L R
authors.initials: LR
authors.lastname: Steranka
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D016308:Enkephalin, Leucine-2-Alanine / Q000378:metabolism; D004745:Enkephalins / Q000378:metabolism; D005508:Food Deprivation; D006168:Guinea Pigs; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000633:toxicity; D009292:Narcotic Antagonists / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011930:Reaction Time / Q000187:drug effects; D012055:Reinforcement Schedule
chemical_list: D004745:Enkephalins; D009292:Narcotic Antagonists; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C068472:naltrexone phenyl oxime; D009271:Naltrexone; D016308:Enkephalin, Leucine-2-Alanine; D009020:Morphine; C038981:nalmefene