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Pharmacological profile of NPC 12626, a novel, competitive N-methyl-D-aspartate receptor antagonist. 1989

J W Ferkany, and D J Kyle, and J Willets, and W J Rzeszotarski, and M E Guzewska, and S R Ellenberger, and S M Jones, and A I Sacaan, and L D Snell, and S Borosky
Nova Pharmaceutical Corporation, Division of Drug Discovery, Baltimore, Maryland.

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.

UI MeSH Term Description Entries
D008297 Male Males
D008566 Membranes Thin layers of tissue which cover parts of the body, separate adjacent cavities, or connect adjacent structures. Membrane Tissue,Membrane,Membrane Tissues,Tissue, Membrane,Tissues, Membrane
D009865 Oocytes Female germ cells derived from OOGONIA and termed OOCYTES when they enter MEIOSIS. The primary oocytes begin meiosis but are arrested at the diplotene state until OVULATION at PUBERTY to give rise to haploid secondary oocytes or ova (OVUM). Ovocytes,Oocyte,Ovocyte
D011919 Rats, Inbred Strains Genetically identical individuals developed from brother and sister matings which have been carried out for twenty or more generations or by parent x offspring matings carried out with certain restrictions. This also includes animals with a long history of closed colony breeding. August Rats,Inbred Rat Strains,Inbred Strain of Rat,Inbred Strain of Rats,Inbred Strains of Rats,Rat, Inbred Strain,August Rat,Inbred Rat Strain,Inbred Strain Rat,Inbred Strain Rats,Inbred Strains Rat,Inbred Strains Rats,Rat Inbred Strain,Rat Inbred Strains,Rat Strain, Inbred,Rat Strains, Inbred,Rat, August,Rat, Inbred Strains,Rats Inbred Strain,Rats Inbred Strains,Rats, August,Rats, Inbred Strain,Strain Rat, Inbred,Strain Rats, Inbred,Strain, Inbred Rat,Strains, Inbred Rat
D001921 Brain The part of CENTRAL NERVOUS SYSTEM that is contained within the skull (CRANIUM). Arising from the NEURAL TUBE, the embryonic brain is comprised of three major parts including PROSENCEPHALON (the forebrain); MESENCEPHALON (the midbrain); and RHOMBENCEPHALON (the hindbrain). The developed brain consists of CEREBRUM; CEREBELLUM; and other structures in the BRAIN STEM. Encephalon
D002545 Brain Ischemia Localized reduction of blood flow to brain tissue due to arterial obstruction or systemic hypoperfusion. This frequently occurs in conjunction with brain hypoxia (HYPOXIA, BRAIN). Prolonged ischemia is associated with BRAIN INFARCTION. Cerebral Ischemia,Ischemic Encephalopathy,Encephalopathy, Ischemic,Ischemia, Cerebral,Brain Ischemias,Cerebral Ischemias,Ischemia, Brain,Ischemias, Cerebral,Ischemic Encephalopathies
D002552 Cerebral Ventricles Four CSF-filled (see CEREBROSPINAL FLUID) cavities within the cerebral hemispheres (LATERAL VENTRICLES), in the midline (THIRD VENTRICLE) and within the PONS and MEDULLA OBLONGATA (FOURTH VENTRICLE). Foramen of Monro,Cerebral Ventricular System,Cerebral Ventricle,Cerebral Ventricular Systems,Monro Foramen,System, Cerebral Ventricular,Systems, Cerebral Ventricular,Ventricle, Cerebral,Ventricles, Cerebral,Ventricular System, Cerebral,Ventricular Systems, Cerebral
D003342 Corpus Striatum Striped GRAY MATTER and WHITE MATTER consisting of the NEOSTRIATUM and paleostriatum (GLOBUS PALLIDUS). It is located in front of and lateral to the THALAMUS in each cerebral hemisphere. The gray substance is made up of the CAUDATE NUCLEUS and the lentiform nucleus (the latter consisting of the GLOBUS PALLIDUS and PUTAMEN). The WHITE MATTER is the INTERNAL CAPSULE. Lenticular Nucleus,Lentiform Nucleus,Lentiform Nuclei,Nucleus Lentiformis,Lentiformis, Nucleus,Nuclei, Lentiform,Nucleus, Lenticular,Nucleus, Lentiform,Striatum, Corpus
D004553 Electric Conductivity The ability of a substrate to allow the passage of ELECTRONS. Electrical Conductivity,Conductivity, Electric,Conductivity, Electrical
D005260 Female Females

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