Subtype-Specific Agonists for NMDA Receptor Glycine Binding Sites

作者：Maolanon Alex R; Risgaard Rune; Wang Shuang Yan; Snoep Yoran; Papangelis Athanasios; Yi Feng; Holley David; Barslund Anne F; Svenstrup Niels; Hansen Kasper B; Clausen Rasmus P^*

来源：ACS Chemical Neuroscience, 2017, 8(8): 1681-1687.

DOI：10.1021/acschemneuro.7b00117

• lonotropic glutamate receptor
• NMDA
• superagonist
• D-serine
• D-cycloserine
• subtype selectivity

A series of analogues based on serine as lead structure were designed, and their agonist activities were evaluated at recombinant NMDA receptor subtypes (GluN1/2A-D) using two-electrode voltage-clamp (TEVC) electrophysiology. Pronounced variation in subunit-selectivity, potency, and agonist efficacy was observed in a manner that was dependent on the GluN2 subunit in the NMDA receptor. In particular, compounds 15a and 16a are potent GluN2C-specific superagonists at the GluN1 subunit with agonist efficacies of 398% and 308% compared to glycine. This study demonstrates that subunit selectivity among glycine site NMDA receptor agonists can be achieved and suggests that glycine-site agonists can be developed as pharmacological tool compounds to study GluN2C-specific effects in NMDA receptor-mediated neurotransmission.

• 出版日期2017-8