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ACS Chem Neurosci
2017 Aug 16;88:1681-1687. doi: 10.1021/acschemneuro.7b00117.
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Subtype-Specific Agonists for NMDA Receptor Glycine Binding Sites.
Maolanon AR
,
Risgaard R
,
Wang SY
,
Snoep Y
,
Papangelis A
,
Yi F
,
Holley D
,
Barslund AF
,
Svenstrup N
,
Hansen KB
,
Clausen RP
.
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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.
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