کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
5815285 | 1115517 | 2012 | 7 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Structure-activity relationships for allosteric NMDA receptor inhibitors based on 2-naphthoic acid Structure-activity relationships for allosteric NMDA receptor inhibitors based on 2-naphthoic acid](/preview/png/5815285.png)
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 â¼Â 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.
⺠2-Naphthoic acid derivatives were found to inhibit NMDA receptor activity. ⺠Structure-activity relationships for optimal inhibitory activity were determined. ⺠Substitutions at the 3-position of 2-naphthoic acid can affect subtype-selectivity. ⺠6-Phenyl substitution in 2-hydroxy-3-naphthoic acid reduces maximal inhibition. ⺠Inhibitory activity is allosteric and does not involve the N-terminal domain.
Journal: Neuropharmacology - Volume 62, Issue 4, March 2012, Pages 1730-1736