title: Neurochemical and electrophysiological studies on FR115427, a novel non-competitive NMDA receptor antagonist.
abstract: The pharmacological profile of FR115427 has been examined using ligand binding and electrophysiological techniques. Binding of [3H]dizocilpine in the presence of L-glutamate was inhibited by the (+) isomers of dizocilpine and FR115427. The corresponding (-) isomers were less active, and stereoselectivity was particularly marked in the case of FR115427. In contrast to dizocilpine, the affinity of FR115427 for [3H]dizocilpine binding sites was little affected by addition of either L-glutamate and/or glycine. In a cortical wedge preparation, FR115427 inhibited N-methyl-D-aspartate (NMDA)-induced responses in a non-competitive, use-dependent manner. Intracellularly recorded excitatory synaptic responses in hippocampal neurones were only partially inhibited by FR115427 thereby confirming a selective effect on the NMDA-mediated component of neuronal excitation induced by the endogenous neurotransmitter. The data suggest that FR115427 is a non-competitive, use-dependent NMDA receptor antagonist with more pronounced stereoselectivity and less marked use dependence than dizocilpine.
authors.affiliation: Fujisawa Institute of Neuroscience, Department of Pharmacology, University of Edinburgh, UK.
authors.forename: J P
authors.initials: JP
authors.lastname: Hodgkiss
authors.forename: H J
authors.initials: HJ
authors.lastname: Sherriffs
authors.forename: D A
authors.initials: DA
authors.lastname: Cottrell
authors.forename: K
authors.initials: K
authors.lastname: Shirakawa
authors.forename: J S
authors.initials: JS
authors.lastname: Kelly
authors.forename: A
authors.initials: A
authors.lastname: Kuno
authors.forename: M
authors.initials: M
authors.lastname: Ohkubo
authors.forename: S P
authors.initials: SP
authors.lastname: Butcher
authors.forename: H J
authors.initials: HJ
authors.lastname: Olverman
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001667:Binding, Competitive; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000378:metabolism / Q000494:pharmacology; D004594:Electrophysiology; D005971:Glutamates / Q000494:pharmacology; D018698:Glutamic Acid; D005998:Glycine / Q000494:pharmacology; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D017966:Pyramidal Cells / Q000187:drug effects* / Q000502:physiology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013237:Stereoisomerism; D009435:Synaptic Transmission / Q000187:drug effects; D044005:Tetrahydroisoquinolines
chemical_list: D005971:Glutamates; D007546:Isoquinolines; D016194:Receptors, N-Methyl-D-Aspartate; D044005:Tetrahydroisoquinolines; C084456:1-methyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline; D018698:Glutamic Acid; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D005998:Glycine