Ifenprodil Stereoisomers: Synthesis, Absolute Configuration, and Correlation with Biological Activity
Ifenprodil Stereoisomers: Synthesis, Absolute Configuration, and Correlation with Biological Activity
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DOI：
10.1021/acs.jmedchem.0c01912
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发表时间：
2021-01-11
影响因子：
7.3
通讯作者：
Wuensch, Bernhard
中科院分区：
文献类型：
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作者：
Bechthold, Elena;Schreiber, Julian A.;Wuensch, Bernhard
艾芬地尔（1）是一种强效的GluN 2B选择性N-甲基-D-天冬氨酸（NMDA）受体拮抗剂，用作脑血管扩张剂，已在临床试验中用于治疗药物成瘾、特发性肺纤维化和COVID-19。为了将生物学数据与构型相关联，所有四种艾芬地尔立体异构体均通过非对映选择性还原和随后通过手性HPLC分离对映异构体来制备。用X-射线单晶衍射法测定了（1 R，2S）-la和（1 S，2S）-1d的绝对构型。评价GluN 2B亲和力、离子通道抑制活性和对α、σ和5-HT受体的选择性。(1R，2 R）-艾芬地尔（（1 R，2 R）-1c）对GluN 2B-NMDA受体表现出最高亲和力（Ki = 5.8 nM），在双电极电压钳实验中对离子通量表现出高度抑制作用（IC 50 = 223 nM）。虽然构型对GluN 2B-NMDA受体结合没有显著影响，但（1 R）-构型对升高的抑制活性至关重要。(1R，2 R）-构型的艾芬地尔（1 R，2 R）-1c对GluN 2B-NMDA受体的选择性高于肾上腺素能、肾上腺素能和sigma（1）受体。
Ifenprodil (1) is a potent GluN2B-selective N-methyl-D-aspartate (NMDA) receptor antagonist that is used as a cerebral vasodilator and has been examined in clinical trials for the treatment of drug addiction, idiopathic pulmonary fibrosis, and COVID-19. To correlate biological data with configuration, all four ifenprodil stereoisomers were prepared by diastereoselective reduction and subsequent separation of enantiomers by chiral HPLC. The absolute configuration of ifenprodil stereoisomers was determined by X-ray crystal structure analysis of (1R,2S)-la and (1S,2S)-1d. GluN2B affinity, ion channel inhibitory activity, and selectivity over alpha, sigma, and 5-HT receptors were evaluated. (1R,2R)-Ifenprodil ((1R,2R)-1c) showed the highest affinity toward GluN2B-NMDA receptors (K-i = 5.8 nM) and high inhibition of ion flux in two-electrode voltage clamp experiments (IC50 = 223 nM). Whereas the configuration did not influence considerably the GluN2B-NMDA receptor binding, (1R)-configuration is crucial for elevated inhibitory activity. (1R,2R)-Configured ifenprodil (1R,2R)-1c exhibited high selectivity for GluN2B-NMDA receptors over adrenergic, serotonergic, and sigma(1) receptors.