The NMDA receptor mediates a slow Ca<sup>2+</sup> permeable component of excitatory synaptic transmission in the central nervous system. Given its central role in many normal and pathological processes, it has been a synthetic target for therapeutically relevant modulators. Recently, a number of unique subunit-selective positive and negative allosteric modulators of NMDA receptors have been described, including TCN-201, a GluN2A-selective negative allosteric modulator that binds to the agonist binding domain dimer interface. Crystallographic analysis of TCN-201 bound to NMDA receptor GluN2A and GluN1 agonist binding domain dimer reveals a unique pose whereby the sulfonamide motif sterically favors a unique pi-stacking between two adjacent aryl groups. We hypothesized that this unique motif might be generally active in aryl binding pockets with sufficient space, and thus tested whether we could extend the SAR of an unrelated series of bi-aryl negative allosteric modulators of NMDA receptor function that are selective for the GluN2C and GluN2D subunits. We therefore added this motif to the NAB series at a position that would allow pi-stacking interactions between aryl rings. After evaluating the potency for inhibiting NMDA receptors, and found that this sulfonamide-linked aryl group was tolerated, and for some analogues, enhanced potency. These results suggest that this motif could be considered in general for binding pockets with space at one end and a critical aryl component.

Sulfonamide motif in NMDA receptor ligands

255th National Meeting (2018)

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