Subunit selective antagonists of NR2A, NR2C, and NR2D containing N-methyl-d-aspartate (NMDA) receptors have not yet been identified and have been confounded by attempting to identify competitive antagonists to a highly conserved agonist binding site. Hansen et al. developed an innovative cell-based calcium release assay configured specifically to identify noncompetitive antagonists and modulators of NMDA receptor function. By use of commercially available libraries and known pharmacologically active agents, they found that some ligands that bind the histamine H3 receptor can also bind the amino-terminal domain of the NR2B NMDA receptor. Highly potent histamine H3 receptor antagonists, e.g., clobenpropit and iodophenpropit, are also NR2B-selective noncompetitive antagonists of NMDA receptors. These studies suggest some level of caution in the interpretation of data generated with these potent histamine H3 receptor antagonists as therapeutic levels may produce some antagonism of NMDA receptors. These results also suggest an intriguing cross-reactivity between certain histamine H3 antagonist and NR2B-containing NMDA receptors, which presents a number of potentially interesting opportunities in terms of drug development.
See article at J Pharmacol Exp Ther 2010, 333:650–662.
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