The effect of competitive antagonist chain length on NMDA receptor subunit selectivity

Bihua Feng, Richard M. Morley, David E. Jane, Daniel T. Monaghan

Research output: Contribution to journalArticle

43 Scopus citations

Abstract

The widely-used N-methyl-d-aspartate (NMDA) receptor antagonists (R)-4-(3-phosphonopropyl) piperazine-2-carboxylic acid ((R)-CPP) and (R)-2-amino-7-phosphonoheptanoate ((R)-AP7) are frequently used as general NMDA receptor antagonists and assumed not to display significant selectivity among NMDA receptor NR2 subunits. However, electrophysiological studies have suggested that certain longer chain N-methyl-d-aspartate (NMDA) receptor competitive antagonists, such as (R)-CPP are ineffective at subpopulations of NMDA receptors in the red nucleus, superior colliculus, and hippocampus. Using recombinant receptors expressed in Xenopus oocytes, we have examined the effect of antagonist chain length on NR2 subunit selectivity. All antagonists displayed the potency order (high to low affinity) of NR2A > NR2B > NR2C > NR2D, however the longer chain antagonists (having 7 instead of 5 bond lengths between acidic groups) displayed much greater subunit selectivity than their short-chain homologues. For example (R)-CPP displayed a 50-fold difference in affinity between NR2A-containing and NR2D-containing NMDA receptors, while the shorter chain homologue 4-(phosphonomethyl) piperazine-2-carboxylic acid (PMPA) displayed only a 5-fold variation in affinity. These results can account for the earlier physiological findings and suggest that longer chain antagonists such as (R)-CPP and (R)-AP7 should not be used as general NMDA receptor antagonists.

Original languageEnglish (US)
Pages (from-to)354-359
Number of pages6
JournalNeuropharmacology
Volume48
Issue number3
DOIs
StatePublished - Mar 2005

Keywords

  • Antagonist
  • CPP
  • Glutamate
  • NMDA
  • NR2
  • Xenopus oocytes

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

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