title: Pharmacological profile of NPC 12626, a novel, competitive N-methyl-D-aspartate receptor antagonist.
abstract: The novel compound 2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid (NPC 12626) was evaluated for activity in a variety of tests associated with receptors for excitatory amino acids. NPC 12626 failed to inhibit the specific binding of RS-[3H] amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid or [3H] kainic acid to brain membranes in vitro but displaced both agonist and antagonist binding to N-methyl-D-aspartic acid (NMDA) receptors. Like cis-(+/-)-3-(2-carboxypiperazine-4-yl)propyl-1-phosphonic acid, NPC 12626 competitively blocked NMDA-induced enhancement of [3H]-1-thienylcyclohexyl)piperidine binding. In the voltage-clamped frog oocyte expression system, NPC 12626 was a competitive inhibitor of NMDA-evoked inward current with a pA2 of 6.24. After both i.c.v. or i.p. administration, NPC 12626 was a potent anticonvulsant in the pentylenetetrazol, maximal electroshock and NMDA seizure models. Furthermore, low doses (25 mg/kg) of NPC 12626 given i.v. were effective in preventing damage to the CA1 region of hippocampus in the gerbil model of global ischemia. Unlike the noncompetitive NMDA antagonist, phencyclidine, but like cis-(+/-)-3-(2-carboxypiperazine-4-yl)propyl-1-phosphonic acid and pentobarbital, NPC 12626 only partially substituted for phencyclidine in a drug discrimination study. The results of the current study indicate that NPC 12626 is a novel, systemically active and competitive NMDA receptor antagonist.
authors.affiliation: Nova Pharmaceutical Corporation, Division of Drug Discovery, Baltimore, Maryland.
authors.forename: J W
authors.initials: JW
authors.lastname: Ferkany
authors.forename: D J
authors.initials: DJ
authors.lastname: Kyle
authors.forename: J
authors.initials: J
authors.lastname: Willets
authors.forename: W J
authors.initials: WJ
authors.lastname: Rzeszotarski
authors.forename: M E
authors.initials: ME
authors.lastname: Guzewska
authors.forename: S R
authors.initials: SR
authors.lastname: Ellenberger
authors.forename: S M
authors.initials: SM
authors.lastname: Jones
authors.forename: A I
authors.initials: AI
authors.lastname: Sacaan
authors.forename: L D
authors.initials: LD
authors.lastname: Snell
authors.forename: S
authors.initials: S
authors.lastname: Borosky
mesh_terms: D000596:Amino Acids / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D002545:Brain Ischemia / Q000503:physiopathology; D002552:Cerebral Ventricles / Q000187:drug effects / Q000502:physiology; D003342:Corpus Striatum / Q000187:drug effects / Q000502:physiology; D004553:Electric Conductivity; D005260:Female; D005849:Gerbillinae; D066298:In Vitro Techniques; D008297:Male; D008566:Membranes / Q000378:metabolism; D016202:N-Methylaspartate; D009865:Oocytes / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D011919:Rats, Inbred Strains; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter / Q000187:drug effects* / Q000378:metabolism; D012640:Seizures / Q000503:physiopathology*; D014981:Xenopus
chemical_list: D000596:Amino Acids; D000927:Anticonvulsants; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; C060212:NPC 12626; D001224:Aspartic Acid; D016202:N-Methylaspartate