Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe University, 06100 Sıhhiye, Ankara, Turkey.
Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Freie Universität Berlin, Königin-Luise-Str. 2+4, 14195 Berlin, Germany.
Bioorg Chem. 2019 Oct;91:103187. doi: 10.1016/j.bioorg.2019.103187. Epub 2019 Aug 7.
1,4-Dihydropyridines (DHPs) are an important class of blockers targeting different calcium channel subtypes and have great therapeutic value against cardiovascular and neurophysiologic conditions. Here, we present the design of DHP-based hexahydroquinoline derivatives as either selective or covalent inhibitors of calcium channels. These compounds were synthesized via a modified Hantzsch reaction under microwave irradiation and characterized by IR, H NMR, C NMR and mass spectra. Additionally, the proposed structure of HM12 was resolved by single crystal X-ray analysis. The abilities of the target compounds to block both L- and T-type calcium channels were evaluated by utilizing the whole-cell patch clamp technique. Our results identified covalent inhibitors of calcium channels for the first time, which could be achieved by introducing a Michael acceptor group into the ester side chain of the compounds. The proposed covalent binding between the compounds and the cysteine amino acid (Cys1492) within the DHP binding pocket of L-type calcium channel was supported by docking and pharmacophore analysis as well as a glutathione reactivity assay.
1,4-二氢吡啶（DHPs）是一类重要的钙通道阻断剂，针对不同的钙通道亚型，在心血管和神经生理疾病的治疗方面具有重要价值。在这里，我们设计了基于 DHP 的六氢喹啉衍生物，作为钙通道的选择性或共价抑制剂。这些化合物通过微波辐射下的改良 Hantzsch 反应合成，并通过红外光谱（IR）、核磁共振氢谱（H NMR）、核磁共振碳谱（C NMR）和质谱进行了表征。此外，HM12 的结构通过单晶 X 射线分析得到解析。利用全细胞膜片钳技术评估了目标化合物对 L 型和 T 型钙通道的阻断能力。我们的研究结果首次鉴定出钙通道的共价抑制剂，这可以通过在化合物的酯侧链中引入迈克尔受体基团来实现。化合物与 L 型钙通道 DHP 结合口袋中半胱氨酸氨基酸（Cys1492）之间的拟议共价结合得到了对接和药效团分析以及谷胱甘肽反应性测定的支持。
