Abstract
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 inXenopus 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.
Footnotes
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Send reprint requests to: Dr. Daniel T. Monaghan, Department of Pharmacology, University of Nebraska Medical Center, 600 S. 42nd Street, Omaha, NE 68198-6260. E-mail:dtmonagh{at}unmc.edu
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↵1 This work was supported by United States Army Medical Research contract DAMD17–94-C-4050 and National Institutes of Health grant NS28966.
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↵2 Eric Harris, Astra, personal communication.
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↵3 Gene Palmer, Astra, personal communication.
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↵4 Gene Palmer, Astra, unpublished observations.
- Abbreviations:
- NMDA
- N-methyl-d-aspartate
- HEPES
- 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
- Received June 7, 1996.
- Accepted October 21, 1996.
- The American Society for Pharmacology and Experimental Therapeutics
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