TY - JOUR T1 - Antagonism of N-Methyl-<span class="sc">d</span>-Aspartate Receptors by ς Site Ligands: Potency, Subtype-Selectivity and Mechanisms of Inhibition JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 326 LP - 338 VL - 282 IS - 1 AU - E. R. Whittemore AU - V. I. Ilyin AU - R. M. Woodward Y1 - 1997/07/01 UR - http://jpet.aspetjournals.org/content/282/1/326.abstract N2 - 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 &gt;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. The American Society for Pharmacology and Experimental Therapeutics ER -