Novel NMDA receptor modulators: an update

Abstract

Introduction: The NMDA receptor is a ligand-gated ion channel that plays a critical role in higher level brain processes and has been implicated in a range of neurological and psychiatric conditions. Although initial studies for the use of NMDA receptor antagonists in neuroprotection were unsuccessful, more recently, NMDA receptor antagonists have shown clinical promise in other indications such as Alzheimer's disease, Parkinson's disease, pain and depression. Based on the clinical observations and more recent insights into receptor pharmacology, new modulatory approaches are beginning to emerge, with potential therapeutic benefit.

Areas covered: The article covers the known pharmacology and important features regarding NMDA receptors and their function. A discussion of pre-clinical and clinical relevance is included, as well. The subsequent patent literature review highlights the current state of the art targeting the receptor since the last review in 2010.

Expert opinion: The complex nature of the NMDA receptor structure and function is becoming better understood. As knowledge about this receptor increases, it opens up new opportunities for targeting the receptor for many therapeutic indications. New strategies and advances in older technologies will need to be further developed before clinical success can be achieved. First-in-class potentiators and subunit-selective agents form the basis for most new strategies, complemented by efforts to limit off-target liability and fine-tune on-target properties.

Figure 1. Homology model of an NMDA receptor

(Top) Schematic representation of the linear amino acid sequence that encodes each subunit. ATD is the amino terminal domain. The S1 and S2 domains fold together to form the ligand binding domain (LBD). M1 through M4 form the transmembrane domain (TMD); M1, M3 and M4 are transmembrane helices and M2 is a re-entrant loop. (Left) Ribbon diagram of homology modeled GluN1-GluN2A NMDA receptor (generated using PyMOL Molecular Graphics System, Version 1.2r3pre, Schrödinger, LLC). The GluN1 subunits are depicted in yellow and the GluN2A subunits are in green. Known modulatory regions are circled and labeled. (Right) Single subunits of GluN1-GluN2 receptor describing the domain architecture. The S1 region of the LBD is in blue and the S2 region is in red.

Figure 2. Ifenprodil

Figure 3. Organic cationic channel blockers

Figure 4. Novel NMDA receptor channel blockers

Figure 5. Glycine-site antagonists recently disclosed by Merz Pharma

Figure 6. GluN2B-selective antagonists disclosed in the patent literature since 2006

Figure 7. GluN2C/D-selective antagonists disclosed in the patent literature since 2010

Figure 8. Phenanthrene and naphthalene compound classes claimed by University of Nebraska

Figure 9. Potentiators of GluN2C/D-containing receptors

Figure 10. Potentiators of NMDA function via spinophilin inhibition

Figure 11. Benzothiadiazepines as unknown site NMDA antagonists

Figure 12. Unknown site inhibitor of NMDA function

Figure 13. Pre-clinical and clinical trial compounds for new indications of NMDA dysfunction