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Blockade by sigma site ligands of N ‐methyl‐D‐aspartate‐evoked responses in rat and mouse cultured hippocampal pyramidal neurones
Author(s) -
Fletcher Elizabeth J.,
Church John,
AbdelHamid Khaled,
MacDonald John F.
Publication year - 1995
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1995.tb15928.x
Subject(s) - ifenprodil , nmda receptor , ampa receptor , kainate receptor , chemistry , sigma receptor , convulsant , dextrorphan , kainic acid , pharmacology , stereochemistry , glutamate receptor , biochemistry , biology , receptor
1 The effects of a range of structurally‐dissimilar compounds which possess affinity for σ binding sites were examined on the responses of cultured hippocampal pyramidal neurones to the excitatory amino acid analogues N ‐methyl‐D‐aspartate (NMDA), kainate and (RS)‐α‐ammo‐3‐hydroxy‐5‐methylisoxazole‐4‐propionic acid (AMPA). 2 In mouse hippocampal neurones under whole‐cell voltage‐clamp, the compounds tested reversibly attenuated NMDA‐, but not kainate‐ or AMPA‐, evoked currents with a rank order potency (IC 50 values in μ m ): ifenprodil (0.8)>(+)‐N‐allylnormetazocine (1.1)>dextromethorphan (1.8) = haloperidol (1.9)>(+)‐pentazocine (7.2)>1 S , 2 R ‐(−)−cis‐N‐methyl‐ N ‐[2‐(3, 4‐dichlorophenyl) ethyl]‐2‐(1‐pyrrolidinyl)cyclohexylamine (17) = rimcazole (18)>1,3‐di(2‐tolyl)guanidine (37)>opipramol (96)>caramiphen (110)=carbetapentane (112)> >(+)‐3‐(3‐hydroxyphenyl)‐ N ‐(1‐propyl)piperidine (485). 3 The attenuation of NMDA‐evoked responses was not mediated through interactions with the agonist, glycine (except haloperidol) or polyamine (except ifenprodil) binding sites on the NMDA receptor‐channel complex but, in the light of the voltage‐ and, in some cases, use‐dependent nature of their antagonism, an interaction with the ion channel appears to be a likely mechanism of action for many of the compounds. 4 Micromolar concentrations of selected σ site ligands also reduced NMDA‐evoked rises in intracellular free calcium concentration in Fura‐2‐loaded cultured hippocampal neurones of the rat with the same rank order potency as observed in the electrophysiological studies. 5 The data indicate that, at micromolar concentrations, the σ site ligands tested act as NMDA receptor antagonists, an action which does not appear to be mediated by high‐affinity σ binding site(s). The functional effects of micromolar concentrations of σ site ligands cannot, therefore, be attributed exclusively to interactions with high‐affinity σ binding sites.