Teleb Mohamed, Zhang Fang-Xiong, Huang Junting, Gadotti Vinicius M, Farghaly Ahmed M, AboulWafa Omaima M, Zamponi Gerald W, Fahmy Hesham
Department of Pharmaceutical Sciences, College of Pharmacy, South Dakota State University, Brookings, SD 57007, USA; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt.
Department of Physiology & Pharmacology, Hotchkiss Brain Institute, University of Calgary, 3330 Hospital Drive NW, Calgary T2N 4N1, Canada.
Bioorg Med Chem. 2017 Mar 15;25(6):1926-1938. doi: 10.1016/j.bmc.2017.02.015. Epub 2017 Feb 13.
Low-voltage-activated calcium channels are important regulators of neurotransmission and membrane ion conductance. A plethora of intracellular events rely on their modulation. Accordingly, they are implicated in many disorders including epilepsy, Parkinson's disease, pain and other neurological diseases. Among different subfamilies, T-type calcium channels, and in particular the Ca3.2 isoform, were shown to be involved in nociceptive neurotransmission. The role of Ca3.2 in pain modulation was supported by demonstrating selective antisense oligonucleotide-mediated Ca3.2 knockdown, in vivo antinociceptive effects of T-type blockers, and pain attenuation in Ca3.2 knockout formalin-induced pain model. These Emerging investigations have provided new insights into targeting T-type calcium channels for pain management. Within this scope, various T-type calcium channel blockers have been developed such as mibefradil and ethosuximide. Although being active, most of these molecules interact with other receptors as well. This addresses the need for T-selectivity. Few selective T-type channel blockers of diverse chemical classes were developed such as ABT-639 and TTA-P2. Interestingly, R(-) efonidipine which is a dihydropyridine (DHP) showed T-channel selectivity. Systematic modification of 1,4-dihydropyridine scaffold introduced novel derivatives with 40-fold T-type selectivity over L-type calcium channels. Along these lines, substitution of the DHP core with various analogues favored T-selectivity and may serve as novel pharmacophores. Several dihydropyrimidine (DHPM) mimics were introduced by Squibb as potential candidates. As a continuation of this approach, the current study describes the synthesis of Novel N3 substituted DHPMs with structure similarities to the active DHPs. Different functional groups were introduced to the N3 position through a spacer to gain more information about activity and selectivity. Furthermore, the spacer aims at improving the metabolic stability of the molecules. Initial screening data by whole patch clamp technique showed a robust inhibition of Ca3.2 T-type channels by eleven compounds. Interestingly, four compounds of these were efficient selective T-type blockers. Based on selectivity and efficiency, two compounds were selected for in vivo evaluation in mouse models of inflammatory pain. Results showed effective attenuation of nociception and mechanical hypersensitivity.
低电压激活钙通道是神经传递和膜离子电导的重要调节因子。大量细胞内事件依赖于它们的调节作用。因此，它们与许多疾病有关，包括癫痫、帕金森病、疼痛及其他神经疾病。在不同的亚家族中，T型钙通道，尤其是Ca3.2亚型，被证明参与伤害性神经传递。通过证明选择性反义寡核苷酸介导的Ca3.2基因敲低、T型阻滞剂的体内抗伤害感受作用以及Ca3.2基因敲除福尔马林诱导疼痛模型中的疼痛减轻，支持了Ca3.2在疼痛调节中的作用。这些新出现的研究为靶向T型钙通道进行疼痛管理提供了新的见解。在此范围内，已开发出各种T型钙通道阻滞剂，如米贝拉地尔和乙琥胺。尽管这些分子具有活性，但它们中的大多数也与其他受体相互作用。这就提出了对T选择性的需求。已开发出少数不同化学类别的选择性T型通道阻滞剂，如ABT - 639和TTA - P2。有趣的是，作为二氢吡啶（DHP）的R(-)依福地平显示出T通道选择性。对1,4 - 二氢吡啶支架的系统修饰引入了对L型钙通道具有40倍T型选择性的新型衍生物。沿着这些思路，用各种类似物取代DHP核心有利于T选择性，并且可作为新型药效基团。施贵宝公司引入了几种二氢嘧啶（DHPM）模拟物作为潜在候选物。作为这种方法的延续，当前研究描述了与活性DHP结构相似的新型N3取代DHPM的合成。通过间隔基团将不同的官能团引入N3位置，以获取更多关于活性和选择性的信息。此外，间隔基团旨在提高分子的代谢稳定性。通过全细胞膜片钳技术的初步筛选数据显示，11种化合物对Ca3.2 T型通道有强烈抑制作用。有趣的是，其中4种化合物是有效的选择性T型阻滞剂。基于选择性和有效性，选择了两种化合物在炎性疼痛小鼠模型中进行体内评估。结果显示伤害感受和机械性超敏反应得到有效减轻。
