Department of Chemistry, Northwestern University, Evanston, IL 60208, USA.
Bioorg Med Chem. 2013 Jul 15;21(14):4365-73. doi: 10.1016/j.bmc.2013.04.054. Epub 2013 Apr 28.
The L-type calcium channel (LTCC) CaV1.3 is regarded as a new potential therapeutic target for Parkinson's disease. Calcium influx through CaV1.3 LTCC during autonomous pacemaking in adult dopaminergic neurons of the substantia nigra pars compacta is related to the generation of mitochondrial oxidative stress in animal models. Development of a CaV1.3 antagonist selective over CaV1.2 is essential because CaV1.2 pore-forming subunits are the predominant form of LTCCs and are abundant in the central nervous and cardiovascular systems. We have explored 1,4-dihydropyrimidines and 4H-pyrans to identify potent and selective antagonists of CaV1.3 relative to CaV1.2 LTCCs. A library of 36 dihydropyridine (DHP)-mimic 1,4-dihydropyrimidines and 4H-pyrans was synthesized, and promising chiral compounds were resolved. The antagonism studies of CaV1.3 and CaV1.2 LTCCs using DHP mimic compounds showed that dihydropyrimidines and 4H-pyrans are effective antagonists of DHPs for CaV1.3 LTCCs. Some 1,4-dihydropyrimidines are more selective than isradipine for CaV1.3 over CaV1.2, shown here by both calcium flux and patch-clamp electrophysiology experiments, where the ratio of antagonism is around 2-3. These results support the hypothesis that the modified hydrogen bonding donor/acceptors in DHP-mimic dihydropyrimidines and 4H-pyrans can interact differently with DHP binding sites, but, in addition, the data suggest that the binding sites of DHP in CaV1.3 and CaV1.2 LTCCs are very similar.
L 型钙通道 (LTCC) CaV1.3 被认为是帕金森病的一个新的潜在治疗靶点。在成年黑质致密部多巴胺能神经元的自主起搏过程中，通过 CaV1.3 LTCC 的钙内流与动物模型中线粒体氧化应激的产生有关。开发对 CaV1.2 具有选择性的 CaV1.3 拮抗剂是至关重要的，因为 CaV1.2 孔形成亚基是 LTCC 的主要形式，并且在中枢神经系统和心血管系统中丰富。我们已经探索了 1,4-二氢嘧啶和 4H-吡喃，以确定相对于 CaV1.2 LTCC 具有高活性和选择性的 CaV1.3 拮抗剂。合成了 36 个二氢吡啶 (DHP)-模拟 1,4-二氢嘧啶和 4H-吡喃的库，并对有前途的手性化合物进行了拆分。使用 DHP 模拟化合物对 CaV1.3 和 CaV1.2 LTCC 的拮抗作用研究表明，二氢嘧啶和 4H-吡喃是 CaV1.3 LTCC 的 DHP 的有效拮抗剂。一些 1,4-二氢嘧啶对 CaV1.3 的选择性比异搏定对 CaV1.2 的选择性更高，这里通过钙通量和膜片钳电生理学实验证明，拮抗作用的比值约为 2-3。这些结果支持了这样的假设，即 DHP 模拟二氢嘧啶和 4H-吡喃中的修改氢键供体/受体可以与 DHP 结合位点以不同的方式相互作用，但此外，数据表明 DHP 在 CaV1.3 和 CaV1.2 LTCC 中的结合位点非常相似。
