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 differing combinations of NR1 and NR2 subunits expressed in Xenopus laevis oocytes. When the NR1 subunit was varied (NR1e/NR2A or NR1b/NR2A), none of the 9 channel blockers tested displayed a statistically different affinity. In contrast, altering NR2 composition changed the affinities of several channel blockers. Three of 10 compounds displayed significantly higher affinities for NR1b/NR2C receptors than NR1b/NR2A receptors, and three of five compounds had higher affinity at NR1b/NR2C than NR1b/NR2B receptors. Both MK-801 and N-[1-(2-thienyl)cyclohyxyl]piperidine displayed identical affinities at all receptor subunit combinations tested. However, these two compounds displayed significantly slower rates of blockade and unblockade at NR1b/NR2C than at NR1b/NR2A receptors, perhaps reflecting the shorter mean open times of NR1/NR2C receptors. NR1b/NR2B and NR1b/NR2A were distinguished by one of five compounds 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.
Monaghan
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DT
Department of Pharmacology, University of Nebraska Medical Center, Omaha 68198-6260, USA. dtmonagh@unmc.edu
Larsen
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D000081:Acetamides / Q000494:pharmacology; D017398:Alternative Splicing; D000818:Animals; D003915:Dextromethorphan / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D018698:Glutamic Acid / Q000494:pharmacology; D005998:Glycine / Q000494:pharmacology; D013287:Illicit Drugs; D007473:Ion Channels / Q000096:biosynthesis / Q000187:drug effects / Q000502:physiology*; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D009865:Oocytes / Q000502:physiology*; D010622:Phencyclidine / Q000031:analogs & derivatives / Q000494:pharmacology; D014176:Protein Biosynthesis; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000096:biosynthesis / Q000187:drug effects / Q000502:physiology*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000187:drug effects; D014158:Transcription, Genetic; D014982:Xenopus laevis
D000081:Acetamides; D018691:Excitatory Amino Acid Antagonists; D013287:Illicit Drugs; D007473:Ion Channels; D016194:Receptors, N-Methyl-D-Aspartate; D011994:Recombinant Proteins; D018698:Glutamic Acid; D003915:Dextromethorphan; C012058:tenocyclidine; C067553:remacemide; D010622:Phencyclidine; D005998:Glycine