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A Novel Negative Allosteric Modulator Selective for GluN2C/2D-Containing NMDA Receptors Inhibits Synaptic Transmission in Hippocampal Interneurons
ACS Chemical Neuroscience ( IF 5 ) Pub Date : 2017-11-02 00:00:00 , DOI: 10.1021/acschemneuro.7b00329
Sharon A. Swanger 1 , Katie M. Vance 1 , Timothy M. Acker 2 , Sommer S. Zimmerman 2 , John O. DiRaddo 1, 2 , Scott J. Myers 1 , Christoffer Bundgaard 3 , Cara A. Mosley 2 , Samantha L. Summer 2 , David S. Menaldino 2 , Henrik S. Jensen 4 , Dennis C. Liotta 2 , Stephen F. Traynelis 1
Affiliation  

N-Methyl-d-aspartate receptors (NMDARs) are ionotropic glutamate receptors that mediate excitatory synaptic transmission and have been implicated in numerous neurological disorders. NMDARs typically comprise two GluN1 and two GluN2 subunits. The four GluN2 subtypes (GluN2A-GluN2D) have distinct functional properties and gene expression patterns, which contribute to diverse functional roles for NMDARs in the brain. Here, we present a series of GluN2C/2D-selective negative allosteric modulators built around a N-aryl benzamide (NAB) core. The prototypical compound, NAB-14, is >800-fold selective for recombinant GluN2C/GluN2D over GluN2A/GluN2B in Xenopus oocytes and has an IC50 value of 580 nM at recombinant GluN2D-containing receptors expressed in mammalian cells. NAB-14 inhibits triheteromeric (GluN1/GluN2A/GluN2C) NMDARs with modestly reduced potency and efficacy compared to diheteromeric (GluN1/GluN2C/GluN2C) receptors. Site-directed mutagenesis suggests that structural determinants for NAB-14 inhibition reside in the GluN2D M1 transmembrane helix. NAB-14 inhibits GluN2D-mediated synaptic currents in rat subthalamic neurons and mouse hippocampal interneurons, but has no effect on synaptic transmission in hippocampal pyramidal neurons, which do not express GluN2C or GluN2D. This series possesses some druglike physical properties and modest brain permeability in rat and mouse. Altogether, this work identifies a new series of negative allosteric modulators that are valuable tools for studying GluN2C- and GluN2D-containing NMDAR function in brain circuits, and suggests that the series has the potential to be developed into therapies for selectively modulating brain circuits involving the GluN2C and GluN2D subunits.

中文翻译:

新型的负变构调节剂选择性GluN2C / 2D包含NMDA受体抑制海马interneurons的突触传递。

N-甲基- ð天冬氨酸受体(NMDAR的)是离子型谷氨酸受体介导的兴奋性突触传递,并且在许多神经系统疾病有牵连。NMDAR通常包含两个GluN1和两个GluN2亚基。四种GluN2亚型(GluN2A-GluN2D)具有不同的功能特性和基因表达模式,这有助于NMDAR在大脑中发挥多种功能作用。在这里,我们介绍了一系列围绕N-芳基苯甲酰胺(NAB)核心构建的GluN2C / 2D选择性负变构调节剂。原型化合物NAB-14对非洲爪蟾卵母细胞中的重组GluN2C / GluN2D的选择性是GluN2A / GluN2B的800倍以上,并具有IC 50在哺乳动物细胞中表达的含有重组GluN2D的受体的580nM的值是最大的。与二异聚体(GluN1 / GluN2C / GluN2C)受体相比,NAB-14抑制三聚体(GluN1 / GluN2A / GluN2C)NMDAR,其效力和功效适度降低。定点诱变表明NAB-14抑制的结构决定因素驻留在GluN2D M1跨膜螺旋中。NAB-14抑制大鼠丘脑下神经元和小鼠海马中间神经元中GluN2D介导的突触电流,但对不表达GluN2C或GluN2D的海马锥体神经元的突触传递没有影响。该系列在大鼠和小鼠中具有类似药物的物理特性和适度的脑通透性。共,
更新日期:2017-11-02
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