Differential binding properties of [3H]dextrorphan and [3H]MK-801 in heterologously expressed NMDA receptors.

摘要: The N-methyl-D-aspartate receptor (NMDAR) antagonists: MK-801, phencyclidine and ketamine are open-channel blockers with limited clinical value due to psychotomimetic effects. Similarly, the effects of dextrorotatory opioids, dextromethorphan its metabolite dextrorphan, derive from their NMDAR antagonist actions. Differences in use dependency blockade, however, suggest that binding sites for MK-801 dextrorphan distinct. In absence exogenous glutamate glycine, rate association [3H]MK-801 wild-type NR1-1a/NR2A receptors was considerably slower than [3H]dextrorphan. Glutamate individually, presence co-agonist had substantial on specific [3H]MK-801, while [3H]dextrorphan not affected. Mutation residues N616 A627 NR1 subunit a profound effect affinity, unaltered. contrast, residues, W611 N812, were critical complexes no corresponding influence [3H]MK-801. Thus, have distinct molecular determinants high-affinity binding. ability bind closed channel, moreover, indicates recognition site is shallower ion channel domain may be associated extracellular vestibule NMDAR.