RT Journal Article
SR Electronic
T1 Identification of AICP as a GluN2C-Selective <em>N</em>-Methyl-<span class="sc">d</span>-Aspartate Receptor Superagonist at the GluN1 Glycine Site
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 151
OP 161
DO 10.1124/mol.117.108944
VO 92
IS 2
A1 Maja Jessen
A1 Kristen Frederiksen
A1 Feng Yi
A1 Rasmus P. Clausen
A1 Kasper B. Hansen
A1 Hans Bräuner-Osborne
A1 Paul Kilburn
A1 Anders Damholt
YR 2017
UL http://molpharm.aspetjournals.org/content/92/2/151.abstract
AB N-methyl-d-aspartate (NMDA)-type ionotropic glutamate receptors mediate excitatory neurotransmission in the central nervous system and are critically involved in brain function. NMDA receptors are also implicated in psychiatric and neurological disorders and have received considerable attention as therapeutic targets. In this regard, administration of d-cycloserine (DCS), which is a glycine site NMDA receptor agonist, can enhance extinction of conditioned fear responses. The intriguing behavioral effects of DCS have been linked to its unique pharmacological profile among NMDA receptor subtypes (GluN1/2A-D), in which DCS is a superagonist at GluN2C-containing receptors compared with glycine and a partial agonist at GluN2B-containing receptors. Here, we identify (R)-2-amino-3-(4-(2-ethylphenyl)-1H-indole-2-carboxamido)propanoic acid (AICP) as a glycine site agonist with unique GluN2-dependent differences in agonist efficacy at recombinant NMDA receptor subtypes. AICP is a full agonist at GluN1/2A (100% response compared with glycine), a partial agonist at GluN1/2B and GluN1/2D (10% and 27%, respectively), and a highly efficacious superagonist at GluN1/2C receptors (353%). Furthermore, AICP potencies are enhanced compared with DCS with EC50 values in the low nanomolar range (1.7 nM at GluN1/2C). We show that GluN1/2C superagonism of AICP and DCS is mediated by overlapping but distinct mechanisms and that AICP selectively enhances responses from recombinant GluN1/2C receptors in the presence of physiological glycine concentrations. This functional selectivity of AICP for GluN2C-containing NMDA receptors is more pronounced compared with DCS, suggesting that AICP can be a useful tool compound for uncovering the roles of GluN2C subunits in neuronal circuit function and in the development of new therapeutic strategies.