Background:The glycine-binding GluN1 and GluN3 subunits of NMDA receptors have distinctive selectivity profiles. Results: TK40 binds to the GluN1 orthosteric binding site and competitively reduces the potency of glycine. Conclusion: TK40 is a novel glycine site antagonist with selectivity for the GluN1 subunit compared with GluN3. Significance: The imino acetamido moiety acts as an ␣-amino acid bioisostere, as predicted by virtual screening.

Ionotropic glutamate receptors (iGluRs) are responsible for most of the fast excitatory communication between neurons in our brain. The GluD2 receptor is a puzzling member of the iGluR family: It is involved in synaptic plasticity, plays a role in human diseases, e.g. ataxia, binds glycine and D-serine with low affinity, yet no ligand has been discovered so far that can activate its ion channel. In this study, we show that the hinge region connecting the two subdomains of the GluD2 ligand-binding domain is responsible for the low affinity of D-serine, by analysing GluD2 mutants with electrophysiology, isothermal titration calorimetry and molecular dynamics calculations. The hinge region is highly variable among iGluRs and fine-tunes gating activity, suggesting that in GluD2 this region has evolved to only respond to micromolar concentrations of D-serine.

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