Neurochemical and electrophysiological studies on FR115427, a novel non-competitive NMDA receptor antagonist.
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.
Hodgkiss
J P
JP
Fujisawa Institute of Neuroscience, Department of Pharmacology, University of Edinburgh, UK.
Sherriffs
H J
HJ
Cottrell
D A
DA
Shirakawa
K
K
Kelly
J S
JS
Kuno
A
A
Ohkubo
M
M
Butcher
S P
SP
Olverman
H J
HJ
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
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