1,4-Dihydropyridine Scaffold in Medicinal Chemistry, The Story so Far And Perspectives (Part 1): Action in Ion Channels and GPCRs

Abstract

Since the pioneering studies of Fleckenstein and co-workers, L-Type Calcium Channel (LTCC) blockers have attracted large interest due to their effectiveness in treating several cardiovascular diseases. Medicinal chemists achieved high potency and tissue selectivity by decorating the 1-4-DHP nucleus, the most studied scaffold among LTCC blockers. Nowadays it is clear that the 1,4-DHP nucleus is a privileged scaffold since, when appropriately substituted, it can selectively modulate diverse receptors, channels and enzymes. Therefore, the 1,4-DHP scaffold could be used to treat various diseases by a single-ligand multi-target approach. In this review, we describe the structure-activity relationships of 1,4-DHPs at ion channels, G-protein coupled receptors, and outline the potential for future therapeutic applications.

Synthesis, Docking Simulation, Biological Evaluations and 3D-QSAR Study of 1,4-Dihydropyridines as Calcium Channel Blockers

“…Various modulators can potentiate or block calcium entry through L-type calcium channels. [4][5][6] Calcium antagonists have a versatile pharmacological activity such as antihypertensive and antianginal, [7][8][9] antitumor, 10,11) anti-inflammatory, 12,13) antitubercular, 14,15) anticonvulsant and antithrombotic. 16,17) 1,4-DHPs bind selectively to L-type calcium channel protein, precisely at the transmembrane domain IIIS6 and IVS6 regions of the α1 subunit.…”

Hibiscus Sabdariffa L. Flowers and Olea Europea L. Leaves Extract-Based Formulation for Hypertension Care: In Vitro Efficacy and Toxicological Profile

“…This latter characteristic is of main importance since calcium channel modulators used in hypertension treatment show high affinity for all calcium channel isoforms with relevant side effects. 32,33 Pres Phytum showed a high tropism toward ileum and colon, showing the same behavior of calcium antagonists, such as dihydropyridines, 32,33 which decrease intestinal motility. Toward respiratory system, Pres Phytum efficacy is inferior than 30% at the maximal studied concentration.…”

“…We speculated that the main mechanism of action of Pres Phytum is represented by its effects toward calcium channels, even if with a lower efficacy compared with nifedipine. 32,33 In addition, the central role of immunity and inflammation in hypertension and vascular diseases has been demonstrated. 36 Also, the increase of reactive oxygen species production contributes to the development and progression of hypertension.…”

Synthesis, utility and medicinal importance of 1,2- & 1,4-dihydropyridines

“…1,4-DHP drugs can be divided into three generations depending on their pharmacologic and pharmacokinetic proles. 122 Because of the short duration and rapid onset of vasodilator action, nifedipine activated sympathetic tone. 123 Therefore, in the quest of better therapeutic standard, the rst-generation drug, nifedipine has been extensively modied.…”