Skip to main content
SpringerLink
Log in

Hydrophobic properties of novel dihydronaphthyridine calcium antagonists and biological activity in porcine isolated cardiac and vascular smooth muscle

  • Original Articles
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Summary

Dihydronaphthyridine calcium antagonists are structurally related to the well known dihydropyridines and act in a similar manner. In order to establish the vascular selectivity of these compounds contractile force was evaluated in porcine isolated ventricular trabeculae and right coronary arteries. The dihydropyridine derivatives nisoldipine and nitrendipine as well as the structurally different compounds gallopamil and flunarizine were included for comparison purpose.

All compounds studied exhibited dose-dependent negative inotropic and vasodilator activities. The negative inotropic potency of all dihydronaphthyridines, especially of the highly lipophilic bulky ester-variated derivatives (Goe 5584-A, Goe 5806-A) was comparable to that of flunarizine but was considerably less pronounced than that of nisoldipine, nitrendipine or gallopamil. By contrast, half-maximal vasodilator responses of the dihydronaphthyridines studied in coronary arteries being in the nanomolar concentration range were comparable to the dihydropyridines nisoldipine and nitrendipine, whereas the activity of gallopamil and flunarizine was less marked. On the other side the dihydronaphthyridines, especially the more hydrophilic 3-ethylester-4-(2-cyanophenyl) derivative Goe 5606, exerted an obvious biphasic concentration-response behaviour in coronary arteries leading to a high affinity relaxant process in subnanomolar concentrations, whereas the low affinity response could be observed at rather high concentrations (mostly > 1 µM). Mainly due to their relative uneffectiveness in cardiac muscle, vascular selectivity of the dihydronaphthyridines was considerably higher than that of the structurally related dihydropyridines nisoldipine resp. nitrendipine increasing in the following order: nitrendipine < nisoldipine < Goe 5606 < Goe 5438< Goe 5584-A < Goe 5806-A. By contrast, gallopamil exerted a slight cardiac preference, whereas the vascular selectivity of flunarizine was also pronounced. Negative inotropic potency of the dihydronaphthyridines decreased with increasing lipophilicity. However, an inverse relationship was found regarding the vasodilator activity of these compounds.

Thus, modulation of the molecular structure, thereby affecting the physicochemical properties, may improve the vascular selectivity of the dihydronaphthyridines studied, when compared to dihydropyridine calcium antagonists.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Bean BP, Sturek M, Puga A, Hermsmeyer K (1986) Calcium channels in muscle cells isolated from rat mesenteric arteries: Modulation by dihydropyridine drugs. Circ Res 59:229–235

    Google Scholar 

  • Bolton TB (1979) Mechanisms of action of transmitter and other substances on smooth muscle. Physiol Rev 59:606–718

    Google Scholar 

  • Bossert F, Horstmann H, Meyer H, Vater W (1979) Einfluβ der Esterfunktion auf die vasodilatierenden Eigenschaften von 1,4-Dihydro-2,6-dimethyl-4-nitrophenyl-pyridin-3,5-dicarbonsäureestern. Arzneim Forsch/Drug Res 29:226–229

    Google Scholar 

  • Cauvin C, Lukeman S, Cameron J, Hwang O, Meisheri K, Yamamoto H, van Breemen C (1984) Theoretical bases for vascular selectivity of Ca-antagonists. J Cardiovasc Pharmacol 6:S630-S638

    Google Scholar 

  • Cauvin CA, van Breemen C (1987) Vascular effects of organic calcium antagonists. ISI Atlas Sci Pharmacol 1:13–19

    Google Scholar 

  • 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 52:1021–1030

    Google Scholar 

  • Droogmans G, Raeymaekers L, Casteels R (1977) Electro- and pharmacomechanical coupling in the smooth muscle cells of rabbit ear artery. J Gen Physiol 70:129–148

    Google Scholar 

  • Fricke U, Klaus W, Stein B (1988) Novel halogenated dihydropyridine derivatives with high vascular selectivity. Naunyn-Schmiedeberg's Arch Pharmacol 338:449–454

    Google Scholar 

  • Fricke U, Ueckert M (1988) Effects of nimodipine, nisoldipine, and halogenated derivatives of nitrendipine in isolated arteries and ventricular muscles of the pig. Naunyn-Schmiedeberg's Arch Pharmacol 338 [Suppl]:R36

    Google Scholar 

  • Glossmann H, Striessnig J, Ferry DR, Goll A, Moosburger K, Schirmer M (1987) Interactions of calcium channels and calcium antagonists. Circ Res 61 [Suppl I]:130–136

    Google Scholar 

  • Godfraind T (1981) Mechanism of action of calcium entry blockers. Fed Proc 40:2866–2871

    Google Scholar 

  • Godfraind (1989) Mechanism of tissue selectivity of calcium antagonists. In: Krieglstein J (ed) Pharmacology of cerebral ischemia 1988. Proceedings of the II. International Symposium on Pharmacology of Cerebral Ischemia, Marburg 1988. Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, pp 45–51

    Google Scholar 

  • Godfraind T, Eglème C, Finet M, Jaumin P (1987) The actions of nifedipine and nisoldipine on the contractile activity of human coronary arteries and human cardiac tissue in vitro. Pharmacol Toxicol 61:79–84

    Google Scholar 

  • Hafner D, Heinen E, Noack E (1977) Mathematical analysis of concentration-response-relationship. Arzneim Forsch/Drug Res 27: 1871–1873

    Google Scholar 

  • Hille B (1977) Local anesthetics: Hydrophilic and hydrophobic pathways for the drug-receptor reaction. J Gen Physiol 69:497–515

    Google Scholar 

  • Hof RP, Scholtysik G, Loutzenhiser R, Vourela HJ, Neumann P (1984) PN-200–110, a new calcium antagonist: electrophysiological, inotropic, and chronotropic effects on guinea pig myocardial tissue and effects on contraction and calcium uptake of rabbit aorta. J Cardiovasc Pharmacol 6:399–406

    Google Scholar 

  • Hondeghem LM, Katzung BG (1977) Time- and voltage-dependent interactions of antiarrhythmic drugs with cardiac sodium channels. Biochim Biophys Acta 472:373–398

    Google Scholar 

  • Huber U (1987) The effects of the Ca-antagonistic compounds Goe 5438 and nimodipine on sinus- and AV node activity. Naunyn-Schmiedeberg's Arch Pharmacol 335 [Suppl]:R52

    Google Scholar 

  • Karasawa A, Kubo K (1988) Calcium antagonistic effects and the in vitro duration of actions of KW 3049, a new 1,4-dihydropyridine derivative, in isolated canine coronary arteries. Jp J Pharmacol 47:35–44

    Google Scholar 

  • Kazda S, Stasch J-P, Hirth C (1987) Experimental pharmacology of nisoldipine: Perspectives from long-term studies. In: Hugenholtz PG, Meyer J (eds) Nisoldipine 1987. Springer, Berlin Heidelberg, pp 3–12

    Google Scholar 

  • Kleinschroth J, Mannhardt K, Hartenstein J, Satzinger G, Wagner B, Muster D, Weinheimer G, Osswald H (1986) 1,4-Dihydro-1,6-naphthyridines, a new class of heterocyclic calcium antagonists. IX. International Symposium on Medicinal Chemistry, Berlin, Abstract 175

  • Klöckner U, Isenberg G (1989) The dihydropyridine niguldipine modulates calcium and potassium currents in vascular smooth muscle cells. Br J Pharmacol 97:957–967

    Google Scholar 

  • Koidl B, Wagner B, Tritthart HA (1988) The inhibitory effects of the novel calcium antagonist Goe 5438 on calcium-dependent processes of excitation and contraction of single cardiomyocytes. Naunyn-Schmiedeberg's Arch Pharmacol 337:447–453

    Google Scholar 

  • Kojda G, Werner G, Fricke U (1989) Einfluβ der Esterfunktion auf die vaskuläre Selektivität von 4-(3-Nitrophenyl)-1,4-dihydropyridinen. Arch Pharm 322:777

    Google Scholar 

  • Kojda G, Klaus W Werner G, Fricke U (1991) The influence of 3-ester side chain variation on the cardiovascular profile of nitrendipine in porcine isolated trabeculae and coronary arteries. Naunyn-Schmiedeberg's Arch Pharmacol (in press)

  • Mannhold R (1983) Kalziumantagonisten vom Typ der aliphatischen Amine und strukturverwandte herzaktive Pharmaka: Untersuchungen zur pharmakologischen und physikalisch-chemischen Charakterisierung. Med Forsch Bd 3: Pharmakologie. Dr. Mannhold, Gelsenkirchen

    Google Scholar 

  • Mannhold R, Bayer R, Ronsdorf M, Martens L (1987) Comparative QSAR studies on vasodilatory and negative inotropic properties of ring-varied verapamil congeners. Arzneim Forsch/Drug Res 37:419–424

    Google Scholar 

  • Marsh JD, Dionne MAM, Chin M, Smith TW (1988) A dihydropyridine calcium channel blocker with phosphodiesterase inhibitory activity: effects on cultured vascular smooth muscle and cultured heart cells. J Mol Cell Cardiol 20:1141–1150

    Google Scholar 

  • Maxwell GM, Crompton S, Reucis V (1982) Effect of nisoldipine on the general and coronary hemodynamics of the anesthetized dog. J Cardiovasc Pharmacol 4:393–397

    Google Scholar 

  • McKenna E, Koch WJ, Slish DF, Schwartz A (1990) Toward an understanding of the dihydropyridine-sensitive calcium channel. Biochem Pharmacol 39:1145–1150

    Google Scholar 

  • Nayler WG (1988) Calcium antagonists. Academic Press, London

    Google Scholar 

  • Nilius B, Hess P, Lansman JB, Tsien RW (1985) A novel type of cardiac calcium channel in ventricular cells. Nature 316:443–446

    Google Scholar 

  • Osswald H, Weinheimer G, Dooley DJ, Preuner H, Kleinschroth J, Mannhardt K, Hartenstein J, Satzinger G (1986) Smooth muscle relaxing and membrane binding characteristic of a new naphthyridine derivate Goe 5438 (CI-951). Naunyn-Schmiedeberg's Arch Pharmacol 334 [Suppl]:R28

    Google Scholar 

  • Osswald H, Muster D, Weinheimer G, Dooley D, Wagner B (1989) Improvement of cerebral microcirculation by the novel specific calcium antagonist CI-951. In: Krieglstein J (ed) Pharmacology of cerebral ischemia 1988. Proceedings of the II. International Symposium on Pharmacology of Cerebral Ischemia, Marburg 1988. Wissenschaftliche Verlagsgesellsehaft mbH, Stuttgart, pp 133–136

    Google Scholar 

  • Repke H, Liebmann C (1987) Membranrezeptoren and ihre Effektorsysteme. VCH Verlagsgesellsehaft, Weinheim

    Google Scholar 

  • 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 t,4-dihydropyridine calcium channel antagonists to their active site. Mol Pharmacol 27:612–623

    Google Scholar 

  • Rodenkirchen R, Bayer R, Steiner R, Bossert F, Meyer H, Möller E (1979) Structure-activity studies on nifedipine in isolated cardiac muscle. Naunyn-Schmiedeberg's Arch Pharmacol 310:69–78

    Google Scholar 

  • Rogart RB, DeBruyn Kops A, Dzau VJ (1986) Identification of two calcium channel receptor sites for [3H]-nitrendipine in mammalian cardiac and smooth muscle membrane. Proc Natl Acad Sci USA 83:7452–7456

    Google Scholar 

  • Sanguinetti MC, Kass RS (1984) Voltage-dependent block of calcium channel current in the calf cardiac Purkinje fiber by dihydropyridine calcium channel antagonists. Circ Res 55:336–348

    Google Scholar 

  • Schächtele Ch, Wagner B, Marmé D (1987) Stereoselective inhibition of calmodulin-dependent cAMP-phosphodiesterase from bovine heart by (+)- and (−)-nimodipine. Naunyn-Schmiedeberg's Arch Pharmacol 335:340–343

    Google Scholar 

  • Schwartz S, Triggle DJ (1984) Cellular action of calcium channel blocking drugs. Ann Rev Med 35:325–329

    Google Scholar 

  • Somlyo AV, Somlyo AP (1968) Electromechanical and pharmacomechanical coupling in vascular smooth muscle. J Pharmacol Exp Ther 159:129–145

    Google Scholar 

  • Taira N (1987) Differences in cardiovascular profile among calcium antagonists. Am J Cardiol 59:24B–29B

  • Towart R (1982) A new method for investigating the isometric contractile responses of small blood vessels. Br J Pharmacol 75:150P

  • Triggle DJ, Janis RA (1987) Calcium channel ligands. Ann Rev Pharmacol Toxicol 27:347–369

    Google Scholar 

  • Triggle DJ, Langs DA, Janis RA (1989) Calcium channel ligands: structure-function relationships of the 1,4-dihydropyridines. Med Res Rev 9:123–180

    Google Scholar 

  • Wagner B, Strumpf G (1986) Effects of the new calcium antagonist Goe 5438 (CI-951) on action potential of guinea pig cardiac tissues. Naunyn-Schmiedeberg's Arch Pharmacol 334 [Suppl]:R29

    Google Scholar 

  • Wagner B, Strumpf G, Koidl B, Tritthart HA (1988) Electrophysiological investigations with the novel calcium antagonist Goe 5584-A in isolate cardiac tissues. Naunyn-Schmiedeberg's Arch Pharmacol 337 [Suppl]:R54

    Google Scholar 

  • Warltier DC, Zyvoloski MG, Gross GJ, Brooks HL (1984) Comparative actions of dihydropyridine slow channel calcium blocking agents in conscious dogs: systemic and coronary hemodynamics with and without combined beta adrenergic blockade. J Pharmacol Exp Ther 230:367–375

    Google Scholar 

  • Werner G, Kojda G, Fricke U (1989) Calcium antagonists of the dihydronaphthyridine type display high vascular selectivity in vitro. Naunyn-Schmiedeberg's Arch Pharmacol 339 [Suppl]:R47

    Google Scholar 

  • Wibo M, DeRoth L, Godfraind T (1988) Pharmacologic relevance of dihydropyridine binding sites in membranes from rat aorta: kinetic and equilibrium studies. Circ Res 62:91–96

    Google Scholar 

Download references

Author information

Author notes

  1. G. Kojda

    Present address: Institut für Pharmakologie der Universität Düsseldorf, Moorenstrasse 5, W4000, Düsseldorf, Germany

Authors and Affiliations

  1. Institut für Pharmakologie der Universität zu Köln, Gleueler Strasse 24, W-5000, Köln 41, Germany

    G. Werner, W. Klaus, G. Kojda & U. Fricke

Authors
  1. G. Werner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. W. Klaus
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. G. Kojda
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. U. Fricke
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

Parts of the results of this paper were presented on the spring meeting of the German Society of Pharmacology and Toxicology in Mainz 1989 (Werner et al. 1989)

Send offprint requests to G. Werner at the above address

Rights and permissions

Reprints and permissions

About this article

Cite this article

Werner, G., Klaus, W., Kojda, G. et al. Hydrophobic properties of novel dihydronaphthyridine calcium antagonists and biological activity in porcine isolated cardiac and vascular smooth muscle. Naunyn-Schmiedeberg's Arch Pharmacol 344, 337–344 (1991). https://doi.org/10.1007/BF00183009

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00183009

Key words

Search

Navigation