Furukawa, Hiro (January 2026) Subtype-selective targeting of NMDA receptors-A potent new compound emerges. The Journal of General Physiology, 158 (1). ISSN 0022-1295
Abstract
Subtype-selective modulation of N-methyl-D-aspartate receptors (NMDARs) remains a major goal in neuropharmacology, with the potential to advance basic research and enable targeted therapies for disorders involving dysregulated glutamatergic signalling. In this volume of the Journal of General Physiology, Lotti et al. describe UCM-101, a newly optimized GluN2A-selective allosteric inhibitor derived from the weakly active scaffold TCN-213. Introduction of a single ethyl group resulted in a 7.5-fold increase in potency, yielding an inhibitor with an IC₅₀ of 110 nM at GluN1/2A receptors and up to 118-fold selectivity over other NMDAR subtypes under physiologically relevant conditions. A 1.7 Å crystal structure of the GluN1-2A ligand-binding domain (LBD) revealed that UCM-101 adopts an extended conformation spanning the inter-subunit allosteric pocket, engaging a previously unexploited "UCM-subsite" distinct from those used by TCN- or MPX-class modulators. Despite its novel orientation, UCM-101 stabilizes the inactive, open-clamshell conformation of the GluN1 LBD, thereby reducing glycine affinity and preventing receptor activation. Mutagenesis identified new selectivity determinants (GluN2A V529, M788, and T797) that are not utilized by TCN-201, demonstrating that different scaffolds exploit distinct microenvironments within the same allosteric site. Functionally, UCM-101 produced robust inhibition of NMDAR-mediated synaptic currents in hippocampal slices (89% at 3 μM) and displayed similar potency at triheteromeric GluN1/2A/2B receptors. Together, these findings validate the mechanistic framework for GluN2A-selective inhibition while broadening the structural landscape for ligand engagement. UCM-101 provides both a potent research tool and a promising scaffold for the development of next-generation subtype-selective NMDAR modulators.
| Item Type: | Paper |
|---|---|
| Subjects: | bioinformatics bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > NMDA receptor bioinformatics > genomics and proteomics > small molecules > NMDA receptor bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types bioinformatics > genomics and proteomics > small molecules |
| CSHL Authors: | |
| Communities: | CSHL labs > Furukawa lab |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 5 January 2026 |
| Date Deposited: | 08 Dec 2025 14:34 |
| Last Modified: | 08 Dec 2025 14:34 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/42028 |
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