Integrated Synthetic, Pharmacological, and Computational Investigation of cis-2-(3,5-Dichlorophenylcarbamoyl)cyclohexanecarboxylic Acid Enantiomers As Positive Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 4
Integrated Synthetic, Pharmacological, and Computational Investigation of cis-2-(3,5-Dichlorophenylcarbamoyl)cyclohexanecarboxylic Acid Enantiomers As Positive Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 4
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DOI：
10.1002/cmdc.201000378
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发表时间：
2011-01-03
期刊：
影响因子：
3.4
通讯作者：
Giraldo, Jesus
中科院分区：
文献类型：
--
作者：
Christov, Christo;Gonzalez-Bulnes, Patricia;Giraldo, Jesus
2-（3，5-二氯苯氨基甲酰基）环己烷羧酸（1）是代谢型谷氨酸受体亚型4（mGluR 4）的有效和选择性正变构调节剂。据报道，1的活性存在于顺式非对映异构体中，其对映异构体形式之间具有相等的效力（Niswender等人，摩尔Pharmacol. 2008，74，1345-1358）。在本研究中，进行了每种顺式对映体的不对称合成，并将它们的活性与外消旋反式进行了比较。在我们的测定中，顺式对映体的效力不同，其中一种（1 R，2S）更高，另一种（1 S，2 R）低于外消旋反式。进行了高水平量子化学计算，以表征所有-异构体构象空间以及构象转变之间的特定中间体。计算分析确定了1的结构特征，可以在mGluR 4功能中发挥作用，并为后续工作奠定了基础，其中分子手性构建在来自活性（1 R，2S）对映异构体的构象上，可以为药物发现提供新思路。实验和理论圆二色光谱之间的比较证实了（1 R，2S）化合物的绝对构型和计算的最稳定构象，从而支持实验和理论工作。
2-(3,5-Dichlorophenylcarbamoyl)cyclohexanecarboxylic acid (1) is a potent and selective positive allosteric modulator of metabotropic glutamate receptor subtype 4 (mGluR4). The activity of 1 was reported to reside in the cis diastereomer with equal potency between its enantiomeric forms (Niswender et al., Mol. Pharmacol. 2008, 74, 1345-1358). In the present study, the asymmetric synthesis of each of the cis enantiomers was performed, and their activities were compared with that of the racemic trans. In our assays, the cis enantiomers differ in potency, with one of them (1R,2S) higher and the other (1S,2R) lower than the racemic trans. High-level quantum chemical calculations were carried out to characterize the structures of minimum energy in all-isomer conformational space as well as particular intermediates between conformational transitions. Computational analysis identified structural features of 1 that can play a role in mGluR4 functionality and establish the basis for subsequent work, in which molecular chirality constructed on conformations derived from those found for the active (1R, 2S) enantiomer can provide new ideas for drug discovery. Comparison between experimental and theoretical circular dichroism spectra confirmed both the absolute configuration of the (1R, 2S) compound and its calculated most stable conformation, thereby supporting experimental and theoretical work.