Pharmacological modulation of NMDA receptor activity and the advent of negative and positive allosteric modulators

Abstract

The NMDA receptor (NMDAR) family of L-glutamate receptors are well known to have diverse roles in CNS function as well as in various neuropathological and psychiatric conditions. Until recently, the types of agents available to pharmacologically regulate NMDAR function have been quite limited in terms of mechanism of action and subtype selectivity. This has changed significantly in the past two years. The purpose of this review is to summarize the many drug classes now available for modulating NMDAR activity. Previously, this included competitive antagonists at the L-glutamate and glycine binding sites, high and low affinity channel blockers, and GluN2B-selective N-terminal domain binding site antagonists. More recently, we and others have identifed new classes of NMDAR agents that are either positive or negative allosteric modulators (PAMs and NAMs, respectively). These compounds include the pan potentiator UBP646, the GluN2A-selective potentiator/GluN2C & GluN2D inhibitor UBP512, the GluN2D-selective potentiator UBP551, the GluN2C/GluN2D-selective potentiator CIQ as well as the new NMDAR-NAMs such as the pan-inhibitor UBP618, the GluN2C/GluN2D-selective inhibitor QZN46 and the GluN2A inhibitors UBP608 and TCN201. These new agents do not bind within the L-glutamate or glycine binding sites, the ion channel pore or the N-terminal regulatory domain. Collectively, these new allosteric modulators appear to be acting at multiple novel sites on the NMDAR complex. Importantly, these agents display improved subtype-selectivity and as NMDAR PAMs and NAMs, they represent a new generation of potential NMDAR therapeutics.

Intracranial Self-Stimulation to Evaluate Abuse Potential of Drugs

“…N-Methyl-D-aspartate Receptor Ligands. The NMDA receptor has at least four types of binding sites relevant to drug action: a glutamate binding site, a glycine binding site, a binding site in the cation channel, and an array of allosteric binding sites (Monaghan et al, 2012). Ligands that bind directly to the glutamate or glycine sites do not facilitate ICSS and may depress ICSS at high doses.…”

“…This apparent discrepancy in abuse-related effects for NMDA channel blockers in ICSS versus drug self-administration procedures would benefit from further study. In addition, studies with newer NMDA receptor allosteric modulators, or with antagonists such as ifenprodil that are selective for NMDA receptor subtypes, have yet to be conducted (Mony et al, 2009;Monaghan et al, 2012).…”

Structural basis of subunit selectivity for competitive NMDA receptor antagonists with preference for GluN2A over GluN2B subunits

“…Considerable progress has been made in the development of subunit-selective allosteric modulators (7)(8)(9)(10)(11)(12)(13), but the development of subtype-selective competitive NMDA receptor antagonists has been less successful. The competitive glutamate-site antagonist NVP-AAM077 (hereafter NVP) was originally reported to have 100-fold preference for GluN1/2A over GluN1/2B (14).…”

New Horizons in Therapeutic Antibody Discovery: Opportunities and Challenges versus Small-Molecule Therapeutics

“…The issue of receptor subtype selectivity is one factor that has driven the pursuit of SM allosteric modulators, [93][94][95] since classically targeted orthosteric sites tend to be more highly conserved across GPCR subfamilies. Identification of SM drugs with allosteric mechanisms of action came about primarily with the increasing use of functional screening assays, 96,97 but it is becoming increasingly evident that antibodies can also exhibit such modulatory effects.…”

“…95,96 With regard to the latter, there is an interesting report of a CXCR1 (class A GPCR) antibody that binds the receptor N-terminal region and can block interleukin 8 (IL-8)-mediated functional responses but has no detectable effects on ligand binding. 98 Allosteric mechanisms affect many target types besides GPCRs, such as ligand-gated ion channels (e.g., GABA A 99 ; NMDA 94 ), receptor tyrosine kinases (RTKs) (e.g., insulin receptor 100 ), and enzymes. They generally involve modulation of an orthosteric ligand, although some allosterics can induce direct effects in their own right, such as observations of antibody-induced internalization of mGluR7 class C 185 Conformational change on ligand binding allows association with G proteins and coupling to intracellular signaling pathways, depending on Gα subunit.…”