Bladen Chris, Gündüz Miyase Gözde, Şimşek Rahime, Şafak Cihat, Zamponi Gerald W
Department of Physiology & Pharmacology, Hotchkiss Brain Institute, University of Calgary, 3330 Hospital Drive NW, Calgary, T2N 4N1, Canada.
Pflugers Arch. 2014 Jul;466(7):1355-63. doi: 10.1007/s00424-013-1376-z. Epub 2013 Oct 23.
1,4-Dihydropyridines (DHPs) are an important class of L-type calcium channel blockers that are used to treat conditions such as hypertension and angina. Their primary target in the cardiovascular system is the Cav1.2 L-type calcium channel isoform, however, a number of DHPs also block low-voltage-activated T-type calcium channels. Here, we describe the synthesis of a series of novel DHP derivatives that have a condensed 1,4-DHP ring system (hexahydroquinoline) and report on their abilities to block both L- and T-type calcium channels. Within this series of compounds, modification of a key ester moiety not only regulates the blocking affinity for both L- and T-type channels, but also allows for the development of DHPs with 30-fold selectivity for T-type channels over the L-type. Our data suggest that a condensed dihydropyridine-based scaffold may serve as a pharmacophore for a new class of T-type selective inhibitors.
1,4-二氢吡啶（DHPs）是一类重要的L型钙通道阻滞剂，用于治疗高血压和心绞痛等病症。它们在心血管系统中的主要靶点是Cav1.2 L型钙通道亚型，然而，许多DHPs也能阻断低电压激活的T型钙通道。在此，我们描述了一系列具有稠合1,4-二氢吡啶环系统（六氢喹啉）的新型DHP衍生物的合成，并报告了它们阻断L型和T型钙通道的能力。在这一系列化合物中，关键酯部分的修饰不仅调节了对L型和T型通道的阻断亲和力，还使得能够开发出对T型通道的选择性比对L型通道高30倍的DHPs。我们的数据表明，基于稠合二氢吡啶的支架可能作为一类新型T型选择性抑制剂的药效基团。
