Research Article 4-Pyridinio-1,4-Dihydropyridines as Calcium Ion Transport Modulators: Antagonist, Agonist, and Dual Action Ilona Domracheva , 1 Iveta Kanepe-Lapsa , 1 Reinis Vilskersts , 2 Imanta Bruvere, 3 Egils Bisenieks, 3 Astrida Velena , 3 Baiba Turovska, 4 and Gunars Duburs 3 1 Latvian Institute of Organic Synthesis, Group of Experimental Chemotherapy, Aizkraukles Iela 21, Riga, Latvia LV-1006 2 Latvian Institute of Organic Synthesis, Laboratory of Pharmaceutical Pharmacology, Aizkraukles Iela 21, Riga, Latvia LV-1006 3 Latvian Institute of Organic Synthesis, Laboratory of Membrane Active Compounds and β-Diketones, Aizkraukles Iela 21, Riga, Latvia LV-1006 4 Latvian Institute of Organic Synthesis, Laboratory of Physical-Organic Chemistry, Aizkraukles Iela 21, Riga, Latvia LV-1006 Correspondence should be addressed to Ilona Domracheva; ilona@farm.osi.lv and Astrida Velena; astrida@osi.lv Received 25 January 2019; Revised 23 December 2019; Accepted 24 February 2020; Published 27 March 2020 Guest Editor: Marc Le Borgne Copyright © 2020 Ilona Domracheva et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. A set of six new 4-pyridinio-1,4-dihydropyridine (1,4-DHP) compounds has been synthesized. The calcium channel modulating activity of these compounds was evaluated in an aorta vascular smooth muscle cell line (A7R5), in an isolated rat aortic ring model, and in human neuroblastoma cell lines (SH-SY5Y). The antagonistic effect of these 1,4-DHP was tested by modulating the impact of carbachol-dependent mobilization of intracellular Ca 2+ in SH-SY5Y cells. The intracellular free Ca 2+ concentration was measured in confluent monolayers of SH-SY5Y cells and A7R5 cells with the Ca 2+ -sensitive fluorescent indicator Fluo-4 NW. Only four compounds showed calcium channel blocking activity in SH-SY5Y and A7R5 cells as well as in the aortic ring model. Among them, compound 3 was the most active calcium channel antagonist, which had 3 times higher activity on carbachol-activated SH-SY5Y cells than amlodipine. Two of the compounds were inactive. Compound 4 had 9 times higher calcium agonist activity than the classic DHP calcium agonist Bay K8644. The intracellular mechanism for the action of compound 4 using inhibitor analysis was elucidated. Nicotinic as well as muscarinic receptors were not involved. Sarcoplasmic reticulum (ER) Ca 2+ (SERCA) stores were not affected. Ryanodine receptors (RyRs), another class of intracellular Ca 2+ releasing channels, participated in the agonist response evoked by compound 4. The electrooxidation data suggest that the studied compounds could serve as antioxidants in OS. 1. Introduction The dihydropyridines (DHPs), especially 1,4-DHP, are a class of polyfunctional (pleiotropic) redox-active organic compounds. 1,4-DHP is an analogue of 1,4-dihydronicotinamide and model compounds of redox-coenzymes NAD(P)H, which participates in redox reactions and can act as deactivators (quenchers) of reactive oxygen species (ROS) and reactive nitrogen species (RNS) [1]. 1,4-DHP is widely used as pharmaceuticals because of their cardiac inotropic and vasomotor effects. Numerous members of this class are important commercial cardiopro- tectors, vasodilators, and calcium antagonists [2, 3], modu- lating not only metabolic pathways that involve Ca 2+ ions [2], including voltage-operating (VOC), receptor-operating (ROC), and store-operating (SOC) calcium channels, but also acting on other targets: alpha-/beta-adrenoreceptors, potassium channels [2], as well as being effectors of oxidative stress (OS) [1, 4]. Homeostasis of Ca 2+ ions is important for metabolic functions in living cells [5]. Under the conditions of OS, this homeostasis is disrupted. Therefore, DHP com- pounds that modulate the transport of Ca 2+ ions [6] may indirectly protect against OS lesions in vascular, cardiac, and other tissues. Hindawi Oxidative Medicine and Cellular Longevity Volume 2020, Article ID 2075815, 14 pages https://doi.org/10.1155/2020/2075815