3D-QSAR Study of 1,4-Dihydropyridines Reveals Distinct Molecular Requirements of Their Binding Site in the Resting and the Inactivated State of Voltage-Gated Calcium Channels

  • Klaus-Jürgen Schleifer
  • Edith Tot
  • Hans-Dieter Höltje

Abstract

Voltage-gated calcium channels (VGCC) are transmembrane proteins that mediate the calcium influx in response to membrane depolarization and thereby initiate cellular activities such as secretion, contraction, and gene expression. According to pharmacological and electrophysiological results they may be divided into the distinct L-, N-, P/Q-, R-, and T-type subfamilies. While all VGCC are composed of the pore-forming α1 subunits, the disulfide-linked α2δ subunits and the intracellular β subunits, only the skeletal muscle L-type channel has an additional transmembrane γ subunit. A second special feature of L-type channels is their unique reaction to the calcium entry blockers such as 1,4-dihydropyridines (DHP), phenylalkylamines and benzothiazepines that are therapeutically used against hypertension, angina pectoris and supraventricular arrhythmias, and the exceptional DHP channel activators (Bay k 8644, RS30026, CGP 28392 or Bay y 5959). However it is not the unique L-type γ subunit which is the physiological target of these compounds, but specific regions of the α1 subunit.

Keywords

Entropy Tyrosine Glycine Carboxylate Carbonyl 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Goldmann, S.,and Stoltefuß, J., 1991, 1,4-Dihydropyridine: Einfluß von Chiralität und Konformation auf Calcium-antagonistische und -agonistische Wirkung, Angew. Chem. 103:1587.CrossRefGoogle Scholar
  2. Kwon, Y.W., Franckowiak, G., Langs, D.A., Hawthorn, M., Joslyn, A., and Triggle, D.J., 1989, Pharmacologie and radioligand binding analysis of actions of 1,4-dihydropyridine activators related to Bay K 8644 in smooth muscle, cardiac muscle and neuronal preparations, Naunyn-Schmiedeberg’s Arch. Pharmacol. 339: 19.Google Scholar
  3. Searle, M.S., and Williams, D.H., 1992, The cost of conformational order: entropy changes in molecular associations, J. Am. Chem. Soc. 114: 10690.CrossRefGoogle Scholar
  4. Still, W.C., Tempczyk, A., Hawley, R.C., and Hendrickson, T., 1990, Semianalytical treatment of solvation for molecular mechanics and dynamics, J. Am. Chem. Soc. 112: 6127.CrossRefGoogle Scholar
  5. Zheng, W., Stoltefuss, J., Goldmann, S., and Triggle, D.J., 1992, Pharmacologie and radioligand binding studies of 1,4-dihydropyridines in rat cardiac and vascular preparations: stereoselectivity and voltage dependence of antagonist and activator interactions, Mol. Pharmacol. 41: 535.Google Scholar

Copyright information

© Springer Science+Business Media New York 2000

Authors and Affiliations

  • Klaus-Jürgen Schleifer
    • 1
  • Edith Tot
    • 1
  • Hans-Dieter Höltje
    • 1
  1. 1.Institute for Pharmaceutical ChemistryHeinrich-Heine-University DüsseldorfDüsseldorfGermany

Personalised recommendations