Binding mechanism investigations guiding the synthesis of novel condensed 1,4-dihydropyridine derivatives with L-/T-type calcium channel blocking activity.

Abstract

Nifedipine and isradipine are prominent examples of calcium channel blockers with a 1,4-dihydropyridine (DHP) scaffold. Although successfully used in clinics since decades for the treatment of hypertension, the binding mechanism to their target, the L-type voltage-gated calcium channel Cav1.2, is still incompletely understood. Recently, novel DHP derivatives with a condensed ring system have been discovered that show distinct selectivity profiles to different calcium channel subtypes. This property renders this DHP class as a promising tool to achieve selectivity towards distinct calcium channel subtypes. In this study, we identified a common binding mode for prominent DHPs nifedipine and isradipine using docking and pharmacophore analysis that is also able to explain the structure-activity relationship of a small subseries of DHP derivatives with a condensed ring system. These findings were used to guide the synthesis of twenty-two novel DHPs. An extensive characterization using 1H NMR, 13C NMR, mass spectra and elemental analysis was followed by whole cell patch clamp assays for analyzing activity at Cav1.2 and Cav3.2. Two compounds were identified with significant activity against Cav1.2. Additionally, we identified four compounds active against Cav3.2 of which three were selective over Cav1.2. Novel binding modes were analyzed using docking and pharmacophore analysis as well as molecular dynamics simulations.

• Authors: David Schaller, Miyase Gözde Gündüz, Fang Xiong Zhang, Gerald W Zamponi, Gerhard Wolber
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 155 Pg. 1-12 (Jul 15 2018) ISSN: 1768-3254 [Electronic] France
• PMID: 29843108 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Chemical References

• Calcium Channel Blockers
• Calcium Channels, L-Type
• Calcium Channels, T-Type
• Dihydropyridines
• 1,4-dihydropyridine

Topics

• Binding Sites (drug effects)
• Calcium Channel Blockers (chemical synthesis, chemistry, pharmacology)
• Calcium Channels, L-Type (metabolism)
• Calcium Channels, T-Type (metabolism)
• Dihydropyridines (chemical synthesis, chemistry, pharmacology)
• Dose-Response Relationship, Drug
• Humans
• Molecular Structure
• Structure-Activity Relationship