N-methyl-D-aspartate (NMDA) receptors are glutamate-gated cation-selective ion channels which mediate the slow component of fast excitatory neurotransmission. NMDARs with different GluN2 subunits (named GluN2A through 2D) are expressed in nearly every type of neuron throughout all regions of the brain. Though many subunit-selective allosteric modulators exist for each of the four GluN2 subtypes, there are currently no positive allosteric modulators that are fully selective for GluN2B-containing NMDARs. Loss of function mutations in the GluN2B subunit have been observed in patients with schizophrenia, autism spectrum disorder, epilepsy, and intellectual disability. Multiple lines of both pharmacological and genetic evidence suggest a strong role of NMDAR hypofunction in the glutamate hypothesis of schizophrenia, although it remains unclear which GluN2 subtype contributes the most to circuital dysfunction. The lack of a pharmacological tool to selectively potentiate GluN2B-containing NMDA receptors limits our ability to fully probe their involvement in the etiology and pathology of these disorders as well as their roles in healthy brain functions. Furthermore, all currently approved therapeutics targeting NMDARs are channel blockers possessing no subunit selectivity and thus elicit numerous side effects; new subunit-selective modulators are needed to minimize the potential for these adverse effects. Using electrophysiology methods in heterologous expression systems, we are characterizing the structural and chemical determinants of a unique inversion of activity phenomenon for GluN2B-selective negative allosteric modulators (NAMs) which results from multiple independent single amino acid substitutions in the modulator binding pocket. We seek to use this new information, together with recently published structural data and <i>in silico</i> methods, to identify the physical mechanism of NAM activity inversion, enabling the search for a novel GluN2B-selective positive allosteric modulator (PAM).

Mechanisms of GluN1/GluN2B NMDA receptor allosteric modulation: In search of a novel PAM

ACS Fall 2021

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