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
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DOI：
10.1016/j.neuropharm.2011.11.019
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发表时间：
2012-03-01
影响因子：
4.7
通讯作者：
Monaghan, Daniel T.
中科院分区：
文献类型：
--
作者：
Costa, Blaise Mathias;Irvine, Mark W.;Monaghan, Daniel T.
N-甲基-D-天冬氨酸(NMDA)受体的过度激活与许多神经系统疾病密切相关，因此开发NMDA受体拮抗剂引起了人们的极大兴趣。我们最近发现了一系列通过一种新的作用机制对NMDA受体进行变构调节的萘系和菲咯酸类化合物。在本研究中，我们确定了18个萘酸衍生物对四种GluN1/GluN2(A-D)NMDA受体亚型的抑制能力的构效关系。2-萘甲酸在含GluN2A的受体上活性较低，在其他NMDA受体上活性较低。2-萘甲酸的3-氨基加成，特别是3-羟基加成，增加了对GluN1/GluN2C和GluN1/GluN2D受体的抑制活性。进一步的卤素和苯基取代2-羟基-3-萘甲酸导致了几个相对有效的抑制剂，其中最有效的是UBP 618NMDA酸)，在每个(1-bromo-2-hydroxy-6-phenylnaphthalene-3-carboxylic受体亚型上的IC_(50)类似于2微米M。虽然UBP618是非选择性的，但UBP618中羟基的消除，如UBP628和UBP608，导致GluN1/GluN2A选择性增加。在所评价的化合物中，特别是那些具有6-苯基取代的化合物，对GluN1/GluN2A、GluN1/GluN2B和GluN1/GluN2C反应的完全抑制能力较差(最大抑制率为60-90%)。这些拮抗剂可能通过不过度阻断NMDA受体信号而潜在地减少不良反应。总之，这些研究揭示了NMDA受体变构拮抗作用的离散结构-活性关系，这可能有助于开发适用于各种神经精神和神经疾病的NMDA受体调节剂。(C)2011爱思唯尔有限公司。保留所有权利。
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 similar to 2 mu M 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. (c) 2011 Elsevier Ltd. All rights reserved.