title: 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 IC(50) ∼ 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.
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, 985800 Nebraska Medical Center, Omaha, NE 68198-5800, USA. bmathiascosta@unmc.edu
authors.forename: Blaise Mathias
authors.initials: BM
authors.lastname: Costa
authors.forename: Mark W
authors.initials: MW
authors.lastname: Irvine
authors.forename: Guangyu
authors.initials: G
authors.lastname: Fang
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Eaves
authors.forename: Maria Belen
authors.initials: MB
authors.lastname: Mayo-Martin
authors.forename: Bodo
authors.initials: B
authors.lastname: Laube
authors.forename: David E
authors.initials: DE
authors.lastname: Jane
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Monaghan
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D004305:Dose-Response Relationship, Drug; D009281:Naphthalenes / Q000494:pharmacology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014981:Xenopus
chemical_list: D009281:Naphthalenes; D016194:Receptors, N-Methyl-D-Aspartate; C030037:2-naphthoic acid