Structure-activity relationships and pharmacophore model of a noncompetitive pyrazoline containing class of GluN2C/GluN2D selective antagonists.
Structure-activity relationships and pharmacophore model of a noncompetitive pyrazoline containing class of GluN2C/GluN2D selective antagonists.
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DOI：
10.1021/jm400652r
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发表时间：
2013-08-22
影响因子：
7.3
通讯作者：
Liotta DC
中科院分区：
文献类型：
--
作者：
Acker TM;Khatri A;Vance KM;Slabber C;Bacsa J;Snyder JP;Traynelis SF;Liotta DC
在这里，我们描述了一类含吡唑啉的二氢喹诺酮负变构调节剂的NMDA受体，显示出较强的亚基选择性的GluN 2C-和GluN 2D-含有受体的GluN 2A-和GluN 2B-含有受体的合成和构效关系。该类的几个成员在纳摩尔范围内抑制NMDA受体反应，并且对GluN 1/GluN 2A和GluN 1/GluN 2B NMDA受体以及AMPA、红藻氨酸、GABA、甘氨酸、烟碱、5-羟色胺和嘌呤能受体的选择性超过50倍。对更有效和选择性的化合物之一的纯化的对映异构体的分析表明，S-对映异构体比R-对映异构体更有效和更选择性。S-对映体对含GluN 2D和GluN 2C受体的IC 50值分别为0.17-0.22 µM，显示出超过70倍的选择性。这类化合物的亚基选择性应该是有用的，在生理和病理生理条件下，在特定的脑回路中定义的作用的GluN 2C-和GluN 2D-含有受体。
Here we describe the synthesis and structure-activity relationship for a class of pyrazoline-containing dihydroquinolone negative allosteric modulators of the NMDA receptor that show strong subunit-selectivity for GluN2C- and GluN2D-containing receptors over GluN2A-and GluN2B-containing receptors. Several members of this class inhibit NMDA receptor responses in the nanomolar range, and are more than 50-fold selective over GluN1/GluN2A and GluN1/GluN2B NMDA receptors, as well as AMPA, kainate, GABA, glycine, nicotinic, serotonin, and purinergic receptors. Analysis of the purified enantiomers of one of the more potent and selective compounds shows that the S-enantiomer is both more potent and more selective than the R-enantiomer. The S-enantiomer had an IC50 value of 0.17–0.22 µM at GluN2D- and GluN2C-containing receptors, respectively, and showed over 70-fold selectivity over other NMDA receptor subunits. The subunit-selectivity of this class of compounds should be useful in defining the role of GluN2C- and GluN2D-containing receptors in specific brain circuits in both physiological and patho-physiological conditions.