Structure-Activity Relationship Study of Subtype-Selective Positive Modulators of K(Ca)2 Channels.
Structure-Activity Relationship Study of Subtype-Selective Positive Modulators of K(Ca)2 Channels.
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DOI：
10.1021/acs.jmedchem.1c01473
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发表时间：
2022-01-13
影响因子：
7.3
通讯作者：
Zhang M
中科院分区：
文献类型：
--
作者：
El-Sayed NS;Nam YW;Egorova PA;Nguyen HM;Orfali R;Rahman MA;Yang G;Wulff H;Bezprozvanny I;Parang K;Zhang M
通过用不同的4-取代环己烷、酪氨酸类似物或单、二卤苯基环取代环己烷部分，合成了一系列修饰的n-环己基-2-（3,5-二甲基吡唑-1-基）-6-甲基嘧啶-4-胺（CyPPA）类似物，并研究了它们对KCa2通道活性的增强作用。在n -苯- n -[2-（3,5-二甲基吡唑-1-酰基）-6-甲基-4-嘧啶胺衍生物中，化合物2q中苯取代4-嘧啶胺的2和5位卤素修饰对KCa2.2a通道的效价比母体模板CyPPA高10倍，而化合物20中苯取代4-嘧啶胺的3和4位卤素取代对KCa2.2a通道的效价比母体模板CyPPA高7倍。两种化合物均保留KCa2.2a/KCa2.3亚型选择性。在初步评价的基础上，选择化合物20和2q在脊髓小脑性共济失调2型（SCA2）电生理模型中进行测试。这两种化合物都能使SCA2小鼠小脑片中的浦肯野细胞异常放电正常化，这表明这些化合物在治疗共济失调症状方面具有潜在的治疗作用。
A series of modified N-cyclohexyl-2-(3,5-dimethyl-1H-pyrazol-1-yl)-6-methylpyrimidin-4-amine (CyPPA) analogs were synthesized by replacing the cyclohexane moiety with different 4-substituted cyclohexane rings, tyrosine analogs, or mono- and dihalophenyl rings, and were subsequently studied for their potentiation of KCa2 channel activity. Among the N-benzene-N-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-4-pyrimidinamine derivatives, halogen decoration at positions 2 and 5 of benzene-substituted 4-pyrimidineamine in compound 2q conferred ~10-fold higher potency, while halogen substitution at positions 3 and 4 of benzene-substituted 4-pyrimidineamine in compound 2o conferred ~7-fold higher potency on potentiating KCa2.2a channels, compared to the parent template CyPPA. Both compounds retained the KCa2.2a/KCa2.3 subtype selectivity. Based on the initial evaluation, compounds 2o and 2q were selected for testing in an electrophysiological model of spinocerebellar ataxia type 2 (SCA2). Both compounds were able to normalize abnormal firing of Purkinje cells in cerebellar slices from SCA2 mice, suggesting the potential therapeutic usefulness of these compounds for treating symptoms of ataxia.
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影响因子：
14.5
作者：
Mochel, Fanny;Rastetter, Agnes;Depienne, Christel
通讯作者：
Depienne, Christel
影响因子：
5.7
作者：
Cho, Lily T. -Y.;Alexandrou, Aristos J.;Young, Gareth T.
通讯作者：
Young, Gareth T.
在清醒的转基因小鼠中对小脑Purkinje细胞自发性射击的体内分析，该小鼠模拟了2型脊椎动物共济失调。
影响因子：
4
作者：
Egorova PA;Gavrilova AV;Bezprozvanny IB
通讯作者：
Bezprozvanny IB
影响因子：
4.6
作者：
Nam YW;Baskoylu SN;Gazgalis D;Orfali R;Cui M;Hart AC;Zhang M
通讯作者：
Zhang M
影响因子：
30.8
作者：
Huynh, DP;Figueroa, K;Pulst, SM
通讯作者：
Pulst, SM