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)


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.


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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Affolter H, Coronado R (1985) Agonists of Bay K8644 and CGP 28392 open calcium channels from skeletal muscle transverse tubules. Biophys J 48:341–357PubMedCrossRefGoogle Scholar
  2. Affolter H, Coronado R (1986) The sidedness of reconstituted calcium channels from muscle transverse tubules as determined by D-600 and D-890 blockade. Biophys J 49:197aCrossRefGoogle Scholar
  3. Bean BP (1984) Nitrendipine block of cardiac calcium channels: high-affinity binding to the inactivated state. Proc Natl Acad Sci USA 81:6388–6392PubMedCrossRefGoogle Scholar
  4. Belleman P, Schade A, Towart R (1983) Dihydropyridine receptor in rat brain labeled with [3H] nimodipine. Proc Natl Acad Sci USA 80:2356–2360CrossRefGoogle Scholar
  5. Bently KL, Thompson LK, Klebe RJ, Horowitz PM (1985) Fluorescence polarization: a general method for measuring ligand binding and membrane microviscosity. Biotechniques 3:356–366Google Scholar
  6. Campbell KP, Sharp AH, Kahl SD (1987) Anti-dihydropyridine antibodies exhibit [3H] nitrendipine binding properties similar to the membrane receptor for the l,4-dihydropyridine Ca2+ channel antagonists. J Cardiovasc Pharm 9:S113-S121CrossRefGoogle Scholar
  7. Chatelain P, Ferreira J, Laurel R, Ruysschaert JM (1986) Amiodarone induced modifications of the phospholipid physical state. A fluorescence polarization study. Biochem Pharm 35:3007–3013PubMedCrossRefGoogle Scholar
  8. Chester DW, Tourtellotte ME, Melchior DL, Romano AH (1986) The influence of saturated fatty acid modulation of bilayer physical state on cellular and membrane structure and function. Biochim Biophys Acta 860:383–398PubMedCrossRefGoogle Scholar
  9. Chester DW, Herbette LG, Mason RP, Joslyn AF, Triggle DJ, Koppel DE (1987) Diffusion of dihydropyridine calcium channel antagonists in cardiac sarcolemmal lipid multibilayers. Biophys J 52:1021–1030PubMedCrossRefGoogle Scholar
  10. Colvin RA, Ashavaid TF, Herbette LG (1985) Structure function studies of canine cardiac sarcolemmal membranes. I. Estimation of receptor site densities. Biochim Biophys Acta 812:601–608PubMedCrossRefGoogle Scholar
  11. Cooper CL, Vandaele S, Barhanin J, Fosset M, Lazdunski M, Hosey MM (1987) Purification and characterization of the dihydropyridine-sensitive voltage-dependent calcium channel from cardiac tissue. J Biol Chern 262:509–512Google Scholar
  12. Cullis PR, De Kruijff B (1979) Lipid polymorphism and the functional roles of lipids in biological membranes. Biochim Biophys Acta 559:399–420PubMedGoogle Scholar
  13. Curtis BM, Catterall WA (1984) Purification of the calcium antagonist receptor of the voltagesensitive calcium channel from skeletal muscle transverse tubules. Biochemistry 23:2113–2118PubMedCrossRefGoogle Scholar
  14. Curtis BM, Catterall WA (1986) Reconstitution of the voltage-sensitive calcium channel purified from skeletal muscle transverse tubules. Biochemistry 25:3077–3083PubMedCrossRefGoogle Scholar
  15. Flockerzi V, Oeken H-J, Hofmann F, Pelzer D, Cavalie A, Trautwein W (1986) Purified dihydropyridine- binding site from skeletal muscle T-tubules is a functional calcium channel. Nature 323:66–68PubMedCrossRefGoogle Scholar
  16. Frenzel J, Arnold K, Nuhn P (1978) Calorimetric, 13C NMR and 31p NMR studies on the interaction of some phenothiazine derivatives with dipalmitoyl phosphatidylcholine model membranes. Biochim Biophys Acta 507:185–197PubMedCrossRefGoogle Scholar
  17. Giraudat J, Dennis M, Heidmann T, Haumont PY, Lederer F, Changeux JP (1987) Structure of the high-affinity binding site for noncompetitive blockers of the acetylcholine receptor. [3HjChlorpromazine labels homologous residues in the beta and delta chains. Biochemistry 26:2410–2418PubMedCrossRefGoogle Scholar
  18. Goldstein DB (1984) The effects of drugs on membrane fluidity. Ann Rev Pharm Toxical 24:43–64CrossRefGoogle Scholar
  19. Hamilton SL, Yatini A, Brush K, Schwartz A, Brown AM (1987) A comparison between the binding and electrophysiological effects of dihydropyridines on cardiac membranes. Mol Pharm 31 :221–231Google Scholar
  20. Herbette LG, Katz AM, Sturtevant JM (1983) Comparison of the interaction of propranolol and timolol with model and biological membrane systems. Mol Pharm 24:259–269Google Scholar
  21. Herbette LG, MacAlister T, Ashavaid TF, Colvin RA (1985) Structure-function studies of canine cardiac sarcolemmal membranes. II. Structural organization of the sarcolemmal membrane as determined by electron microscopy and lamellar X-ray diffraction. Biochim Biophys Acta 812:609PubMedCrossRefGoogle Scholar
  22. Herbette LG, Chester DW, Rhodes DG (1986) Structural analysis of drug molecules in biological membranes. Biophys J 49:91–93PubMedCrossRefGoogle Scholar
  23. Herbette LG, Trumbore M, Chester DW, Katz AM (1988) Possible molecular basis for the pharmacokinetics and pharmacodynamics of three membrane-active drugs: propranolol, nimodipine and amiodarone. J Mol Cell Card, in pressGoogle Scholar
  24. Hess P, Lansman lB, Fox AP, Nowycky MC, Nilius B, McCleskey EW, Tsien RW (1985) Calcium channels: mechanisms of modulation and ion permeation. J Gen Physiol 86:5saGoogle Scholar
  25. Hof RP, Reugg UT, Hof A, Vogel A (1985) Stereoselectivity at the calcium channel: opposite action of the enantiomers of a l,4-dihydropyridine. J Cardiovasc Pharm 7:689–693CrossRefGoogle Scholar
  26. Höltje H-D, Marrer S (1987) A molecular graphics study on structure-action relationships of calciumantagonistic and agonistic l,4-Dihydropyridines. J Computer-Aided Mol Design 1:23–30CrossRefGoogle Scholar
  27. Horne WA, Weiland GA, Oswald RE (1986) Solubilization and hydrodynamic characterization of the dihydropyridine receptor from rat ventricular muscle. J Biol Chern 261:3588–3594Google Scholar
  28. Imagawa P, Leung AT, Campbell KP (1987) Phosphorylation ofthe 1,4-dihydropyridinereceptor of the voltage dependent calcium channel by an intrinsic protein kinase in isolated triads from rabbit skeletal muscle. J Biol Chern 262:8333–8339Google Scholar
  29. Janis RA, Rampe D, Sarmiento JG, Triggle DJ (1984) Specific binding of a calcium channel activator, [3Hj Bay K8644, to membranes from cardiac muscle and brain. Biochem Biophys Res Comm 121:317–323PubMedCrossRefGoogle Scholar
  30. Janis RA, Scriabine A (1983) Sites of action of Ca2+ channel inhibitors. Biochem Pharmacal 32:3499–3507CrossRefGoogle Scholar
  31. Janis RA, Triggle DJ (1984) l,4-Dihydropyridine Ca2+ channel antagonists and activators: a comparison of binding characteristics with pharmacology. Drug Dev Res 4:5425–5437CrossRefGoogle Scholar
  32. Kokubun S, Reuter H (1984) Dihydropyridine derivatives prolong the open state of Ca ++ channels in cultured cardiac cells. Proc Natl Acad Sci USA 81:4824–4827PubMedCrossRefGoogle Scholar
  33. Kolb VM, Koman A, Terenius L (1983) Fluorescent probes for opioid receptors. Life Sci 33:423–426PubMedCrossRefGoogle Scholar
  34. Kongsamut S, Kamp TJ, Miller RJ, Sanquinetti MC (1985) Calcium channel agonist and antagonist effects of the stereoisomers of the dihydropyridine 202–791. Biochem Biophys Res Comm 130:141–148PubMedCrossRefGoogle Scholar
  35. Koppel DE (1979) Fluorescence redistribution after photobleaching. A new multipoint analysis of membrane translational dynamics. Biophys J 28:281–292PubMedCrossRefGoogle Scholar
  36. Koppel DE, Sheetz MP (1983) A localized pattern photo bleaching method for the concurrent analysis of rapid and slow diffusion processes. Biophys J 43: 175–181PubMedCrossRefGoogle Scholar
  37. Langs DA, Triggle DJ (1985) Conformational features of calcium channel agonist and antagonist analogs of nifedipine. Mol Pharm 27:544–548Google Scholar
  38. Lee KS, Tsien RW (1983) Mechanism of calcium channel blockade by verapamil, D-600, diltiazem and nitrendipine in single dialysed heart cells. Nature 302:790–794PubMedCrossRefGoogle Scholar
  39. Leung AT, Imagawa T, Campbell KP (1987) Structural characterization of the 1,4-dihydropyridine receptor of the voltage-dependent Ca2+ channel from rabbit skeletal muscle. Evidence for two ditinct high molecular weight subunits. J Bioi Chem 262:7943–7946Google Scholar
  40. Mason RP, Chester DW (1988) Diffusional dynamics of an active rhodamine-labelled 1,4-dihydropyridine in sarcolemmal lipid multibilayers. Effects of the rhodamine substituent and multibilayer dehydration on ligand diffusion. Submitted ManuscriptGoogle Scholar
  41. McClosky M, Poo M-M (1986) Rates of membrane associated reactions: reduction of dimensionality revisited. J Cell Bioi 102:88–96CrossRefGoogle Scholar
  42. Morton ME, Caffrey JM, Brown AM, Frochrer SC (1988) Monoclonal antibody to the alphal-1subunit of the dihydropyridine-binding complex inhibits calcium currents in BC3HI myocytes. J Bioi Chem 263:613–616Google Scholar
  43. Rebek Jr, J (1987) Model studies in molecular recognition. Science 235:1478–1484PubMedCrossRefGoogle Scholar
  44. Reuter H, Porzig H, Kokobun S, Prod’om B (1985) Voltage dependence of dihydropyridine ligand binding and action in intact cardiac cells. J Gen Physiol 86:5aGoogle Scholar
  45. Rhodes DG, Sarmiento JG, Herbette LG (1985) Kinetics of binding of membrane-active drugs to receptor sites. Diffusion limited rates for a membrane bilayer approach of l,4-dihydropyridine calcium channel antagonists to their active site. Mol Pharm 27:612–623Google Scholar
  46. Rosenberg RL, Hess P, Reeves JP, Smilowitz H, Tsien RW (1986) Calcium channels in planar lipid bilayers: insights into mechanisms of ion permeation and gating. Science 231:1564–1566PubMedCrossRefGoogle Scholar
  47. Shaafi RI, Fernandez SM (1983) Fast methods in physical biochemistry and cell biology. Elsevier, AmsterdamGoogle Scholar
  48. Schmid A, Barhanin I, Coppola T, Borsotto M, Lazdunski M (1986) Immunochemical analysis of subunit structures of l,4-dihydropyridine receptors associated with voltage-dependent Ca2+ channels in skeletal, cardiac, and smooth muscles. Biochemistry 25:3492–3495PubMedCrossRefGoogle Scholar
  49. Sharp AH, Imagawa T, Leung AT, Campbell KP (1987) Identification and characterization of the dihydropyridine-binding subunit of the skeletal muscle dihydropyridine receptor. J Bioi Chem 262:12309–12315Google Scholar
  50. Takahashi M, Catterall WA (1987) Dihydropyridine-sensitive calcium channels in cardiac and skeletal muscle membranes: studies with antibodies against the alpha subunits. Biochemistry 26:5518–5526PubMedCrossRefGoogle Scholar
  51. Tanabe T, Takeshima H, Mikami A, Flockerzi V, Takahashi H, Kangawa K, Kojima M. Matsuo H, Hirose T, Numa S (1987) Primary structure of the receptor for calcium channel blockers from skeletal muscle. Nature 328:313–318PubMedCrossRefGoogle Scholar
  52. Triggle AM, Shefter E, Triggle DJ (1980) Crystal structures of calcium channel antagonists: 2,6- dimethyl-3,5-dicarbomethoxy-4- [2-nitro-, 3-cyano, 4-(dimethylamino)-, and 2,3,4,5,6- pentafluorophenyl]- 1,4-dihydropyridine. J Med Chem 23:442–445CrossRefGoogle Scholar
  53. Trumbore MW, Chester DW, Rhodes D, Herbette LG (1988) The structure and location of amiodarone in a membrane bilayer as determined by molecular mechanics and quantitative X-Ray diffraction. Biophys J, in pressGoogle Scholar
  54. Venter JC, Fraser CM, Schaber JS, Yung CY, Bolger G, Triggle DJ (1983) Molecular properties of the slow inward calcium channel. I. Molecular weight determination by radiation inactivation nd covalent affinity labeling. J Biol Chem 258:9344–9348PubMedGoogle Scholar
  55. Valdivia H, Coronado R (1988) Pharmacological profile of skeletal muscle calcium channels in planar lipid bilayers. Biophys J 53:555aGoogle Scholar
  56. Vilven J, Leung AT, Imagawa T, Sharp AH, Campbell KP, Coronado R (1988) Interaction of calcium channels of skeletal muscle with monoclonal antibodies specific for its dihydropyridine receptor. Biophys J 53:556aGoogle Scholar

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

Personalised recommendations