Di-aryl Sulfonamide Motif Adds π-Stacking Bulk in Negative Allosteric Modulators of the NMDA Receptor

Abstract

The N-methyl-d-aspartate receptor plays a critical role in central nervous system processes. Its diverse properties, as well as hypothesized role in neurological disease, render NMDA receptors a target of interest for the development of therapeutically relevant modulators. A number of subunit-selective modulators have been reported in the literature, one of which is TCN-201, a GluN2A-selective negative allosteric modulator. Recently, it was determined from a cocrystallization study of TCN-201 with the NMDA receptor that a unique active pose exists in which the sulfonamide group of TCN-201 incorporates a π-π stacking interaction between the two adjacent aryl rings that allows it to make important contacts with the protein. This finding led us to investigate whether this unique structural feature of the diaryl sulfonamide could be incorporated into other modulators that act on distinct pockets. To test whether this idea might have more general utility, we added an aryl ring plus the sulfonamide linker modification to a previously published series of GluN2C- and GluN2D-selective negative allosteric modulators that bind to an entirely different pocket. Herein, we report data suggesting that this structural modification of the NAB-14 series of modulators was tolerated and, in some instances, enhanced potency. These results suggest that this motif may be a reliable means for introducing a π-π stacking element to molecular scaffolds that could improve activity if it allowed access to ligand-protein interactions not accessible from one planar aromatic group.

Figure 1

Structures of known NMDAR channel blockers and negative allosteric modulators; memantine (1), dextromethorphan (2), amantadine (3), ketamine (4) ifenprodil (5),^, DQP-1105 (6), QNZ-46 (7), NAB-14 (8), TCN-201 (9, a GluN2A-selective negative allosteric modulator that acts by reducing glycine affinity), and EVT-101 (10).

Figure 2

Structures and activities from first-generation NAB-14 analogs with planar third-ring extensions. Data are for GluN1/GluN2D (n = 6 oocytes).

Figure 3

Conformational searchs results for TCN-201 (9) and the diaryl sulfonamides comparing the shapes adopted when sulfonamide and amide linkers of two different lengths are used. (A) Lowest-energy conformer for each TCN-201 (9) (left) and compound 26 (right), a compound in which the sulfonamide of TCN-201 has been replaced with an amide. (B) Lowest-energy conformer for each 23 (upper) and the corresponding analog 27 (lower) in which the sulfonamide is replaced by an amide. (C) All 50 conformers resulting from the conformational search for compound 18 containing a methylene in the sulfonamide linker (left) and compound 23 containing an ethylene in the sulfonamide linker (right) are superimposed.

Scheme 1

Figure 4

Structures of compounds 18, 26, 23, and 27.