Abstract
Recent studies propose that ς site ligands antagonize N-methyl-d-aspartate (NMDA) receptors by either direct, or indirect mechanisms of inhibition. To investigate this question further we used electrical recordings to assay actions of seventeen structurally diverse ς site ligands on three diheteromeric subunit combinations of cloned rat NMDA receptors expressed inXenopus oocytes: NR1a coexpressed with either NR2A, 2B or 2C. The ς site ligands had a wide range of potency for antagonizing NMDA receptor currents. Steady-state IC50 values ranged between ∼0.1 to >100 μM. In all cases inhibition was non-competitive with respect to glycine and glutamate. Five structurally related ς ligands [eliprodil, haloperidol, ifenprodil, 4-phenyl-1-(4-phenylbutyl)-piperidine and trifluperidol] were strongly selective for NR1a/2B receptors. The other drugs were weakly selective or nonselective inhibitors. There was no correlation between ς site affinity and potency of NMDA receptor antagonism for any subunit combination. Inhibition of NR1a/2B receptors by the selective antagonists was independent of voltage whereas inhibition by the weakly selective antagonists was voltage dependent. Potency of 10 ς ligands was cross-checked on NMDA currents in cultured rat cortical neurons. There was close correspondence between the two assay systems. Our results argue that antagonism of NMDA receptor currents by the ς ligands tested is due to direct effects on the receptor channel complex as opposed to indirect effects mediated by ς receptors. Inhibition occurs via sites in the NMDA receptor channel pore, or via allosteric modulatory sites associated with the NR2B subunit.
Footnotes
-
Send reprint requests to: Dr. Richard Woodward, Cocensys Pharmaceuticals Inc., Hitachi Chemical Research Center, 1003, Health Sciences Road West, Irvine, CA 92715.
- Abbreviations:
- BD 1008
- N-[2-(3,4-dichlorophenyl)-ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine
- DTG
- 1,3-di(2-tolyl)guanidine
- 4-IBP
- N-(N-benzyl-piperidin-4yl)-4-iodobenzamide
- IPAG
- 1-(4-iodophenyl)-3-(1-adamantyl)guanidine
- NMDA
- N-methyl-d-aspartate
- PCP
- phencyclidine
- 4-PPBP
- 4-phenyl-1-(4-phenylbutyl)-piperidine
- R(+)- and S(−)-3-PPP
- R(+)- and S(−)-3-(3-hydroxyphenyl)-N-propylpiperidine
- (+)- and (−)-SKF 10
- 047, (+)- and (−)-N-allylnormetazocine
- HEPES
- N-2-hydroxyethylpiperazine-N′-2-ethanesulphonic acid
- Received October 24, 1996.
- Accepted March 7, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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Antagonism of N-Methyl-d-Aspartate Receptors by ς Site Ligands: Potency, Subtype-Selectivity and Mechanisms of Inhibition
