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Review
. 2014 Dec;24(12):1349-66.
doi: 10.1517/13543776.2014.972938. Epub 2014 Oct 29.

NMDA receptor modulators: an updated patent review (2013-2014)

Katie L Strong  1 , Yao Jing, Anthony R Prosser, Stephen F Traynelis, Dennis C Liotta
Affiliations
Review

NMDA receptor modulators: an updated patent review (2013-2014)

Katie L Strong et al. Expert Opin Ther Pat. 2014 Dec.

Abstract

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 capable of regulating 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 intersubunit 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.

Keywords: NMDA receptor subunit-selective antagonists; NMDA receptor subunit-selective positive modulators; channel blockers; deuterated analogs; glycine site antagonists; glycine transport inhibitors.

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Figures

Figure 1
Figure 1. Homology Model of an NMDA receptor highlighting known binding sites
Ribbon diagram depicting the NMDA receptor where the GluN1 subunit is shown in blue and the GluN2 subunit is shown in grey. (The figure was generated using the GluN2B crystal structure, PDB 4PE5). Known or postulated binding sites are shown for several classes of ligands. The binding sites for zinc (the cleft of the GluN2A,B bilobed ATD), UPB compounds (the LBD), endogenous polyamines (the GluN2B ATD) are not shown. We also have not shown structural determinants of action for the endogenous neurosteroid pregnenolone sulfate, which has been suggested to involve helices J/K in the S2 portion of the LBD in addition to residues near the M4 transmembrane helix or the structural determinants for the negative allosteric modulation that appear to reside in the S2 region of the LBD.
Figure 2
Figure 2
NMDA receptor channel blockers.
Figure 3
Figure 3
Subunit-selective antagonists.
Figure 4
Figure 4
Subunit-selective allosteric modulators.
Figure 5
Figure 5
Novel NMDA channel blockers.
Figure 6
Figure 6
Merz Pharma developed glycine site antagonist.
Figure 7
Figure 7
GLYX-13 analogs disclosed by Northwestern University.
Figure 8
Figure 8
GluN2B subunit-selective compounds disclosed by NeurOp Inc and Bristol-Myers Squibb.
Figure 9
Figure 9
Ifenprodil based compounds disclosed by Cold Springs Harbor Laboratory.
Figure 10
Figure 10
Novel GluN2C subunit-selective potentiators disclosed by Emory University.
Figure 11
Figure 11
Positive allosteric oxysterols disclosed by Sage Therapeutics.
Figure 12
Figure 12
Phenoxy-ethyl-amine derivatives disclosed by Integrative Research Laboratories.
Figure 13
Figure 13
GlyT1 inhibitors disclosed by Hoffmann La-Roche
See this image and copyright information in PMC

References

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