Discovery of Michael acceptor containing 1,4-dihydropyridines as first covalent inhibitors of L-/T-type calcium channels

  • Bioorg Chem. 2019 Oct:91:103187. doi: 10.1016/j.bioorg.2019.103187.
Hande Aygün Cevher  1 ,  David Schaller  2 ,  Maria A Gandini  3 ,  Ozan Kaplan  4 ,  Eder Gambeta  3 ,  Fang Xiong Zhang  3 ,  Mustafa Çelebier  4 ,  Muhammad Nawaz Tahir  5 ,  Gerald W Zamponi  3 ,  Gerhard Wolber  2 ,  Miyase Gözde Gündüz  6
Affiliations
  • 1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe University, 06100 Sıhhiye, Ankara, Turkey.
  • 2. Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Freie Universität Berlin, Königin-Luise-Str. 2+4, 14195 Berlin, Germany.
  • 3. Department of Physiology & Pharmacology, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, University of Calgary, 3330 Hospital Drive NW, Calgary T2N 4N1, Canada.
  • 4. Department of Analytical Chemistry, Faculty of Pharmacy, Hacettepe University, 06100 Sıhhiye, Ankara, Turkey.
  • 5. Department of Physics, University of Sargodha, Sargodha, Pakistan.
  • 6. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe University, 06100 Sıhhiye, Ankara, Turkey. Electronic address: [email protected].
PMID: 31419643 DOI: 10.1016/j.bioorg.2019.103187
Abstract

1,4-Dihydropyridines (DHPs) are an important class of blockers targeting different Calcium Channel subtypes and have great therapeutic value against cardiovascular and neurophysiologic conditions. Here, we present the design of DHP-based hexahydroquinoline derivatives as either selective or covalent inhibitors of calcium channels. These compounds were synthesized via a modified Hantzsch reaction under microwave irradiation and characterized by IR, 1H NMR, 13C NMR and mass spectra. Additionally, the proposed structure of HM12 was resolved by single crystal X-ray analysis. The abilities of the target compounds to block both L- and T-type calcium channels were evaluated by utilizing the whole-cell patch clamp technique. Our results identified covalent inhibitors of calcium channels for the first time, which could be achieved by introducing a Michael acceptor group into the ester side chain of the compounds. The proposed covalent binding between the compounds and the cysteine amino acid (Cys1492) within the DHP binding pocket of L-type calcium channel was supported by docking and pharmacophore analysis as well as a glutathione reactivity assay.

Keywords
Calcium channel blocker; Covalent binding; Dihydropyridine; Hexahydroquinoline; Molecular modeling; Whole-cell patch clamp.
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