TY - JOUR
T1 - Identification of AICP as a GluN2C-Selective N-methyl-D-aspartate receptor superagonist at the GluN1 glycine site s
AU - Jessen, Maja
AU - Frederiksen, Kristen
AU - Yi, Feng
AU - Clausen, Rasmus P.
AU - Hansen, Kasper B.
AU - Bräuner-Osborne, Hans
AU - Kilburn, Paul
AU - Damholt, Anders
N1 - Funding Information:
This work was supported by H. Lundbeck A/S, Innovation Fund Denmark, University of Montana Research Grant Program, and the National Institutes of Health National Institute of General Medical Sciences [Grant P20GM103546] and National Institute of Neurological Disorders and Stroke [Grant R01NS097536]. The authors thank Pia Maribo Sørensen (H. Lundbeck A/S), Annette Bjørn (H. Lundbeck A/S), and Gina Bullard (University of Montana) for excellent technical assistance, and Trine Kvist Carlino (University of Copenhagen) for kindly providing the mutant rat GluN1 constructs.
PY - 2017/8
Y1 - 2017/8
N2 - 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.
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.
UR - http://www.scopus.com/inward/record.url?scp=85024103539&partnerID=8YFLogxK
U2 - 10.1124/mol.117.108944
DO - 10.1124/mol.117.108944
M3 - Article
C2 - 28588066
AN - SCOPUS:85024103539
SN - 0026-895X
VL - 92
SP - 151
EP - 161
JO - Molecular Pharmacology
JF - Molecular Pharmacology
IS - 2
ER -