Akman Dilara, Denzinger Katrin, Huang Sun, Lee J T, Nafie Jordan W, Wolber Gerhard, Zamponi Gerald W, Armstrong Daniel W, Gündüz Miyase Gözde
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.
Eur J Med Chem. 2022 Dec 15;244:114787. doi: 10.1016/j.ejmech.2022.114787. Epub 2022 Sep 22.
1,4-Dihydropyridines (DHPs) represent the blockbuster class of L-type calcium channel blockers that have tremendous therapeutic value against cardiovascular conditions. Due to their abilities to additionally target other subtypes of calcium channels, DHPs are also considered promising molecules for the treatment of neurological and psychiatric disorders. Having been in the market for more than forty years, DHP is one of the most modified scaffolds for the development of novel molecules acting on calcium channels. Taking the chemical structures of approved DHPs into account, it is noteworthy that C-4 position is the least modified part of the ring system. Therefore, in the present study, we focused on this location and carried out various molecular modifications to obtain twelve potential calcium channel blockers with a DHP-based hexahydroquinoline scaffold (DA1-DA12). The whole-cell patch clamp technique applied to analyze the blocking ability of the synthesized compounds on both L- (Ca1.2) and T- (Ca3.2) type calcium channels revealed five blockers with different selectivity profiles. Introducing naphthyl moiety onto the C-4 position of the main scaffold led to the identification of a selective blocker of Ca1.2 (DA8). The benzodioxole-substituted derivative (DA1) was the most potent and selective Ca3.2 inhibitor, therefore, its enantiomers were separated using HPLC on a chiral stationary phase. Retesting single isomers on Ca3.2 revealed that S-enantiomer was mainly responsible for the block. Finally, DA compounds were docked into two generated homology models of L- and T-type calcium channels. Molecular dynamics (MD) simulations and 3D pharmacophore modeling provided further insights into the detailed binding mechanism of DHPs to Ca1.2 as well as to Ca3.2.
1,4-二氢吡啶（DHPs）是一类重磅级的L型钙通道阻滞剂，对心血管疾病具有巨大的治疗价值。由于它们还能够靶向其他亚型的钙通道，DHPs也被认为是治疗神经和精神疾病的有前景的分子。DHP已上市四十多年，是开发作用于钙通道的新型分子时修饰最多的骨架之一。考虑到已获批的DHPs的化学结构，值得注意的是，C-4位是环系统中修饰最少的部分。因此，在本研究中，我们聚焦于该位置，并进行了各种分子修饰，以获得十二种具有基于DHP的六氢喹啉骨架的潜在钙通道阻滞剂（DA1-DA12）。应用全细胞膜片钳技术分析合成化合物对L型（Ca1.2）和T型（Ca3.2）钙通道的阻断能力，发现了五种具有不同选择性特征的阻滞剂。在主骨架的C-4位引入萘基部分，鉴定出一种Ca1.2的选择性阻滞剂（DA8）。苯并二恶唑取代的衍生物（DA1）是最有效且选择性最高的Ca3.2抑制剂，因此，使用手性固定相通过HPLC分离了其对映体。在Ca3.2上重新测试单一异构体表明，S-对映体是主要的阻断剂。最后，将DA化合物对接至两个生成的L型和T型钙通道同源模型中。分子动力学（MD）模拟和3D药效团建模进一步深入了解了DHPs与Ca1.2以及Ca3.2的详细结合机制。
