Derivatives of (<i>R</i>)‑3-(5-Furanyl)carboxamido-2-aminopropanoic Acid as Potent NMDA Receptor Glycine Site Agonists with GluN2 Subunit-Specific Activity

NMDA receptors mediate glutamatergic
neurotransmission and are
therapeutic targets due to their involvement in a variety of psychiatric
and neurological disorders. Here, we describe the design and synthesis
of a series of (R)-3-(5-furanyl)­carboxamido-2-aminopropanoic
acid analogues 8a–s as agonists at
the glycine (Gly) binding site in the GluN1 subunit, but not GluN3
subunits, of NMDA receptors. These novel analogues display highly
variable potencies and agonist efficacies among the NMDA receptor
subtypes (GluN1/2A–D) in a manner dependent on the GluN2 subunit.
Notably, compound 8p is identified as a potent partial
agonist at GluN1/2C (EC50 = 0.074 μM) with an agonist
efficacy of 28% relative to activation by Gly and virtually no agonist
activity at GluN1/2A, GluN1/2B, and GluN1/2D. Thus, these novel agonists
can modulate the activity of specific NMDA receptor subtypes by replacing
the full endogenous agonists Gly or d-serine (d-Ser),
thereby providing new opportunities in the development of novel therapeutic
agents.