NR1 AND NR2 SUBUNIT CONTRIBUTIONS TO N-METHYL-D-ASPARTATE RECEPTOR-CHANNEL BLOCKER PHARMACOLOGY

The potencies of various N-methyl-D-aspartate (NMDA) receptor channel blockers were determined at recombinant NMDA receptors containing diff ering combinations of NR1 and NR2 subunits expressed in Xenopus laevis oocytes. When the NR1 subunit was varied (NR1e/NR2A or NR1b/NR2A), no ne of the 9 channel blockers tested displayed a statistically differen t affinity. In contrast, altering NR2 composition changed the affiniti es of several channel blockers. Three of 10 compounds displayed signif icantly higher affinities for NR1b/NR2C receptors than NR1b/NR2A recep tors, and three of five compounds had higher affinity at NR1b/NR2C tha n NR1b/NR2B receptors. Both MK-801 and N-[1-(2-thienyl)cyclohyxyl]pipe ridine displayed identical affinities at all receptor subunit combinat ions tested. However, these two compounds displayed significantly slow er rates of blockade and unblockade at NR1b/NR2C than at NR1b/NR2A rec eptors, perhaps reflecting the shorter mean open times of NR1/NR2C rec eptors. NR1b/NR2B and NR1b/NR2A were distinguished by one of five comp ounds tested. Taken together, these results indicate that NR2 subunits impart differing pharmacological profiles to NMDA receptors; thus, it may be possible to develop NMDA receptor channel blocker antagonists of greater subtype selectivity.