Investigation of the structural requirements for N-methyl-D-aspartate receptor positive and negative allosteric modulators based on 2-naphthoic acid.
Investigation of the structural requirements for N-methyl-D-aspartate receptor positive and negative allosteric modulators based on 2-naphthoic acid.
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DOI：
10.1016/j.ejmech.2018.12.054
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发表时间：
2019-02
影响因子：
6.7
通讯作者：
M. Irvine;G. Fang;K. Sapkota;E. Burnell;A. Volianskis;B. Costa;Georgia R. Culley;G. Collingridge;D. Monaghan;D. Jane
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文献类型：
--
作者：
M. Irvine;G. Fang;K. Sapkota;E. Burnell;A. Volianskis;B. Costa;Georgia R. Culley;G. Collingridge;D. Monaghan;D. Jane
n -甲基- d-天冬氨酸受体（NMDAR）是一种由l-谷氨酸和甘氨酸激活的配体门控离子通道，在学习和记忆的突触可塑性中起重要作用。NMDAR与神经退行性疾病如阿尔茨海默病和帕金森病有关，NMDAR功能障碍与精神分裂症有关。本文描述了2-萘酸衍生物的构效关系（SAR）研究，以研究NMDARs的正变构调节和负变构调节的结构要求。这些研究发现了ubp684 （14b）等化合物，它们通过增强含有GluN1和GluN2A-D亚基的二异质NMDAR四聚体中的NMDAR电流而起泛增效作用。其14能带衍生物是研究突触功能的有用工具，并有潜力作为开发治疗精神分裂症和导致认知功能丧失的疾病的药物的线索。此外，SAR研究已经发现了一系列苯乙烯取代的化合物，它们具有部分NAM活性，并且与其他GluN2亚基相比，它们更倾向于抑制GluN2D。其中，3-硝基苯基衍生物ubp783 （79i）和2-硝基苯基衍生物ubp792 （79h）对GluN2D的抑制ic50分别为1.4 μM和2.9 μM，但最大抑制率仅为70-80%。GluN2D已被证明在神经损伤引起的过度疼痛传递中发挥作用，并可能在神经退行性疾病中发挥作用。部分GluN2D抑制剂可能是开发治疗这些疾病的药物的先导，而不会产生完全NMDAR拮抗剂所观察到的不良反应。
TheN-methyl-D-aspartate receptor (NMDAR), a ligand-gated ion channel activated by L-glutamate and glycine, plays a major role in the synaptic plasticity underlying learning and memory. NMDARs are involved in neurodegenerative disorders such as Alzheimer's and Parkinson's disease and NMDAR hypofunction is implicated in schizophrenia. Herein we describe structure-activity relationship (SAR) studies on 2-naphthoic acid derivatives to investigate structural requirements for positive and negative allosteric modulation of NMDARs. These studies identified compounds such asUBP684(14b), which act as pan potentiators by enhancing NMDAR currents in diheteromeric NMDAR tetramers containing GluN1 and GluN2A-D subunits.14band derivatives thereof are useful tools to study synaptic function and have potential as leads for the development of drugs to treat schizophrenia and disorders that lead to a loss of cognitive function. In addition, SAR studies have identified a series of styryl substituted compounds with partial NAM activity and a preference for inhibition of GluN2D versus the other GluN2 subunits. In particular, the 3-and 2-nitrostyryl derivativesUBP783(79i) andUBP792(79h) had IC50s of 1.4 μM and 2.9 μM, respectively, for inhibition of GluN2D but showed only 70–80% maximal inhibition. GluN2D has been shown to play a role in excessive pain transmission due to nerve injury and potentially in neurodegenerative disorders. Partial GluN2D inhibitors may be leads for the development of drugs to treat these disorders without the adverse effects observed with full NMDAR antagonists.