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1,4-Dihydropyridines as Modulators of Voltage-Dependent Calcium-Channel Activity

  • D. W. Chester
  • L. G. Herbettel
Conference paper
Part of the Bayer AG Centenary Symposium book series (BAYER)

Abstract

The interaction of l,4-dihydropyridine (DHP) ligands with their receptors in a variety of tissues has been shown to be highly stereospecific. DHP analogs which differ in substitutions to either the dihydropyridine or aryl ring have markedly different activities and inotropic effects. Moreover, the observation that drug enantiomeric pairs possess opposing inotropic activities suggests a complex interconnection between the ligand structure (orientation/conformation) and the configuration of the receptor-binding domain. In general, these ligands have both high partition coefficients and binding affinities. The pathway of approach for the drug-receptor interaction may dictate the allowable drug conformations and orientations, which would then have an impact on the “success”of drug collisions with a stereos elective binding domain. In particular, ligands which partition into the membrane would be affected by the local microenvironment, producing an energy-minimized eqilibrium conformation and orientation. It is anticipated that the process of bilayer partition is rapid on the receptor-binding time scale, and as such, the conformationallorientational equilibrium would be established long before the actual binding event (see Fig. 3). Knowledge of the contributing factors for bilayer location, orientation, and conformation in concert with structure - function relationships and molecular modeling approaches might facilitate drug design efforts. Drug design, in turn, can have an impact on the clinical efficacy of these ligands as they are used to treat and control cardiovascular abnormalities.

Keywords

Membrane Bilayer Planar Lipid Bilayer Physical Chemical Characteristic Bilayer Location Receptor Site Density 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Springer-Verlag Berlin Heidelberg 1988

Authors and Affiliations

  • D. W. Chester
    • 1
    • 4
  • L. G. Herbettel
    • 1
    • 2
    • 3
    • 4
  1. 1.Department of MedicineUniversity of Connecticut Health CenterFarmingtonUSA
  2. 2.Department of RadiologyUniversity of Connecticut Health CenterFarmingtonUSA
  3. 3.Department of BiochemistryUniversity of Connecticut Health CenterFarmingtonUSA
  4. 4.Department of Biomolecular Structure Analysis CenterUniversity of Connecticut Health CenterFarmingtonUSA

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