Structure-activity relationships for allosteric NMDA receptor inhibitors based on 2-naphthoic acid

Abstract

Over-activation of N-methyl-D-aspartate (NMDA) receptors is critically involved in many neurological conditions, thus there has been considerable interest in developing NMDA receptor antagonists. We have recently identified a series of naphthoic and phenanthroic acid compounds that allosterically modulate NMDA receptors through a novel mechanism of action. In the present study, we have determined the structure-activity relationships of 18 naphthoic acid derivatives for the ability to inhibit the four GluN1/GluN2(A-D) NMDA receptor subtypes. 2-Naphthoic acid has low activity at GluN2A-containing receptors and yet lower activity at other NMDA receptors. 3-Amino addition, and especially 3-hydroxy addition, to 2-naphthoic acid increased inhibitory activity at GluN1/GluN2C and GluN1/GluN2D receptors. Further halogen and phenyl substitutions to 2-hydroxy-3-naphthoic acid leads to several relatively potent inhibitors, the most potent of which is UBP618 (1-bromo-2-hydroxy-6-phenylnaphthalene-3-carboxylic acid) with an IC50 ~ 2 μM at each of the NMDA receptor subtypes. While UBP618 is non-selective, elimination of the hydroxyl group in UBP618, as in UBP628 and UBP608, leads to an increase in GluN1/GluN2A selectivity. Of the compounds evaluated, specifically those with a 6-phenyl substitution were less able to fully inhibit GluN1/GluN2A, GluN1/GluN2B and GluN1/GluN2C responses (maximal % inhibition of 60 – 90%). Such antagonists may potentially have reduced adverse effects by not excessively blocking NMDA receptor signaling. Together, these studies reveal discrete structure-activity relationships for the allosteric antagonism of NMDA receptors that may facilitate the development of NMDA receptor modulator agents for a variety of neuropsychiatric and neurological conditions.

1,6-Dibromonaphthalen-2-ol methanol monosolvate

“…For information on applications of 1,6-dibromo-2-napthol, see: Costa et al (2012); Takeuchi et al (2000); Kalra & Kumar (2005). For related structures, see: Rozycka-Sokolowska & Marciniak (2009).…”

“…Naphthol-containing compounds have gained popularity recently in the pharmaceutical industry as they have potential applications in the synthesis of antipsychotic medications (Costa et al, 2012). The title compound has unique applications as a peroxidase enhancer in peroxidase-catalyzed oxidation reactions (Takeuchi et al, 2000).…”

Structural Determinants and Mechanism of Action of a GluN2C-selective NMDA Receptor Positive Allosteric Modulator

“…The development of GluN2-selective modulators provides a therapeutic opportunity to target NMDAR subtypes with anatomically restricted expression patterns, thereby minimizing potential side effects (Kalia et al, 2008;Ogden and Traynelis, 2011;Collingridge et al, 2013). Subunitselective allosteric modulators exist for the GluN2A (TCN-201), GluN2B (ifenprodil), and GluN2C/GluN2D subunits (6,7-dimethoxy-1-[(4-methoxyphenoxy)methyl]-3,4-dihydroisoquinolin-2(1H)-yl)methanone], QNZ, UBP, DQP analogs) (Williams et al, 1993;Bettini et al, 2010;Mullasseril et al, 2010;Acker et al, 2011;Hansen and Traynelis, 2011;Costa et al, 2012;Hansen et al, 2012;Monaghan et al, 2012). However, no modulators to date have been able to distinguish between GluN2C and GluN2D subunits.…”

Inhibition of GluN2A-Containing N-Methyl-d-Aspartate Receptors by 2-Naphthoic Acid

“…The structural determinants of NPA binding remain unknown. However structure-activity analyses that predate this work revealed that the NPA-binding site on NMDA receptors can accept molecules that are fairly large, geometrically flat and hydrophobic, and have a negatively charged group (Costa et al, 2012). Conversely, functional measurements combined with NMDA receptor mutagenesis indicated that the NPA effects on NMDA receptors are independent of the receptor's N-terminal domain but require the N-terminal segment of the glutamate-binding domain (S1).…”