Mechanism of Action of a GluN2C- and GluN2D-Selective NMDA Receptor Positive Allosteric Modulator

Abstract

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.