Introduction The NMDA receptor mediates a slow component of excitatory synaptic transmission, and NMDA receptor dysfunction has been implicated in numerous neurological disorders. Thus, interest in developing modulators that are able to regulate the channel continues to be strong. Recent research has led to the discovery of a number of compounds that hold therapeutic and clinical value. Deeper insight into the NMDA inter-subunit interactions and structural motifs gleaned from the recently solved crystal structures of the NMDA receptor should facilitate a deeper understanding of how these compounds modulate the receptor. Areas covered This article discusses the known pharmacology of NMDA receptors. A discussion of the patent literature since 2012 is also included, with an emphasis on those that claimed new chemical entities as regulators of the NMDA receptor. Expert Opinion The number of patents involving novel NMDA receptor modulators suggests a renewed interest in the NMDA receptor as a therapeutic target. Subunit-selective modulators continue to show promise, and the development of new subunit-selective NMDA receptor modulators appears poised for continued growth. Although a modest number of channel blocker patents were published, successful clinical outcomes involving ketamine have led to a resurgent interest in low-affinity channel blockers as therapeutics.

The N-methyl-d-aspartate (NMDA) receptor, fundamental for excitatory synaptic transmission, is a tetrameric assembly of two glycine-binding GluN1 subunits and two glutamate-binding GluN2 subunits, of which there are four subtypes (referred to as GluN2A–GluN2D). The GluN2 subunit endows the receptor with unique pharmacological properties and shows distinct developmental and regional expression profiles, which have led to interest in GluN2-selective modulators for the receptor. One recently described compound, (3-chlorophenyl)(6,7-dimethoxy-1-((4-methoxyphenoxy)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (referred to as CIQ), selectively potentiates the response of GluN2C- and GluN2D-containing NMDA receptors to agonist activation. This tetrahydroisoquinoline compound has no agonist activity on its own, and is without effect on GluN2A- and GluN2B-containing NMDA receptors. CIQ was the first positive allosteric modulator for the GluN2C and GluN2D subunits reported in the literature, and since its discovery, multiple investigations have provided insight into its mechanism, site of action, pharmacokinetic properties, and off-target activity. CIQ has also been utilized as a tool compound in animal models of fear learning, schizophrenia, and Parkinson’s disease. The compound is being used to elucidate the role of NMDA receptors in these diseases states and to demonstrate the potential therapeutic benefits of a NMDA receptor positive allosteric modulator.

Subunit-selective inhibition of N-methyl-D-aspartate receptors (NMDARs) is a promising therapeutic strategy for several neurological disorders, including epilepsy, Alzheimer's and Parkinson's disease, depression, and acute brain injury. We previously described the dihydroquinoline−pyrazoline (DQP) analogue 2a (DQP-26) as a potent NMDAR negative allosteric modulator with selectivity for GluN2C/D over GluN2A/B. However, moderate (<100-fold) subunit selectivity, inadequate cellmembrane permeability, and poor brain penetration complicated the use of 2a as an in vivo probe. In an effort to improve selectivity and the pharmacokinetic profile of the series, we performed additional structure−activity relationship studies of the succinate side chain and investigated the use of prodrugs to mask the pendant carboxylic acid. These efforts led to discovery of the analogue (S)-(−)-2i, also referred to as (S)-(−)-DQP-997-74, which exhibits >100-and >300-fold selectivity for GluN2C-and GluN2Dcontaining NMDARs (IC 50 0.069 and 0.035 μM, respectively) compared to GluN2A-and GluN2B-containing receptors (IC 50 5.2 and 16 μM, respectively) and has no effects on AMPA, kainate, or GluN1/GluN3 receptors. Compound (S)-(−)-2i is 5-fold more potent than (S)-2a. In addition, compound 2i shows a time-dependent enhancement of inhibitory actions at GluN2C-and GluN2Dcontaining NMDARs in the presence of the agonist glutamate, which could attenuate hypersynchronous activity driven by highfrequency excitatory synaptic transmission. Consistent with this finding, compound 2i significantly reduced the number of epileptic events in a murine model of tuberous sclerosis complex (TSC)-induced epilepsy that is associated with upregulation of the GluN2C subunit. Thus, 2i represents a robust tool for the GluN2C/D target validation. Esterification of the succinate carboxylate improved brain penetration, suggesting a strategy for therapeutic development of this series for NMDAR-associated neurological conditions.