NEUROCHEMICAL AND ELECTROPHYSIOLOGICAL STUDIES ON FR115427, A NOVEL NONCOMPETITIVE NMDA RECEPTOR ANTAGONIST

被引:21
作者
HODGKISS, JP
SHERRIFFS, HJ
COTTRELL, DA
SHIRAKAWA, K
KELLY, JS
KUNO, A
OHKUBO, M
BUTCHER, SP
OLVERMAN, HJ
机构
[1] UNIV EDINBURGH,DEPT PHARMACOL,FUJISAWA INST NEUROSCI,1 GEORGE SQ,EDINBURGH EH8 9JZ,MIDLOTHIAN,SCOTLAND
[2] UNIV EDINBURGH,DEPT PHARMACOL,EDINBURGH EH8 9YL,MIDLOTHIAN,SCOTLAND
[3] FUJISAWA PHARMACEUT CO LTD,NEW DRUG RES LABS,YODOGAWA KU,OSAKA 532,JAPAN
关键词
NMDA (N-METHYL-D-ASPARTATE); NONCOMPETITIVE ANTAGONISM; DIZOCILPINE; FR115427; CORTICAL WEDGE; HIPPOCAMPUS;
D O I
10.1016/0014-2999(93)90902-T
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
The pharmacological profile of FR115427 has been examined using ligand binding and electrophysiological techniques. Binding of [H-3]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 [H-3]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.
引用
收藏
页码:219 / 227
页数:9
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