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Calcium Antagonists

  • Chapter
Drug Discovery

Abstract

The first drugs to become known as Ca antagonists* were four structurally unrelated substances: verapamil, nifedipine, diltiazem, and perhexiline. The synthesis, pharmacology and initial clinical testing of verapamil as an antianginal agent occurred several years before it was demonstrated to block Ca channels, and a similar sequence was apparently true for nifedipine, diltiazem, and perhexiline (Fleckenstein, 1983; Kendall and Okopski, 1986; Krikler, 1987; Winbury, 1984). Via the use of verapamil (and prenylamine, a weaker, less specific agent), the concept that a dual ionic carrier system existed in mammalian my ocardial fibers (Reuter, 1967; Reuter and Beeler, 1969) was strongly substantiated, and the phenomenon of Ca antagonism was first demonstrated (Fleckenstein et al., 1967, 1969; Fleckenstein, 1983; Kohlhardt et al., 1972). It became clear that, in addition to the well-known “fast” channel for the inward movement of Ca. This slow Ca influx, which was initiated by the action potential spike, acted to trigger the contractile apparatus and thereby linked contraction with membrane excitation in the my ocardium.

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References

  • Antman, E. M., Stone, P. H., Muller, J. E., and Braun wald, E.: Calciumchan-nel blocking agents in the treatment of cardiovascular disorders. Part: basic and clinical electrophysiologic effects. Ann. Intern. Med. 93:875–885, 1980.

    PubMed  CAS  Google Scholar 

  • Benfey, B. G., Greeff, K., and Heeg, E.: Evaluation of sympathetic beta-receptor blockade by recording the rate of ventricular pressure rise in cats. Br. J. Pharmacol. Chemother. 30:23–29, 1967.

    Article  PubMed  CAS  Google Scholar 

  • Bossert, F. and Vater, W.: Dihydropyridine, eine neue Gruppe stark wirksamer Coronartherapeutika. Naturwissenschaften 58:578, 1971.

    Article  PubMed  CAS  Google Scholar 

  • Church, J. and Zsotér, T. T.: Calcium antagonistic drugs. Mechanism of action. Can. J. Physiol. Pharmacol. 58:254–264, 1980.

    CAS  Google Scholar 

  • Cohen, C. J., Janis, R. A., Taylor, D. G., and Scriabine, A.: Where do calcium antagonists act?, in Calcium Antagonists and Cardiovascular Disease, L. H. Opie, ed., pp. 151–163, Raven, New York, 1984.

    Google Scholar 

  • Crawford, M. H.: Effectiveness of diltiazem for chronic stable angina pectoris. Ada Pharmacol. Toxicol. 57 (Suppl. 2): 44–48, 1985.

    Google Scholar 

  • Fleckenstein, A.: Die Bedeutung der energiereichen Phosphate für Kon-traktilität und Tonus des Myokards. Verh. Dtsch. Ges. Inn. Med. 70:81–99, 1964.

    PubMed  CAS  Google Scholar 

  • Fleckenstein, A.: Specific inhibitors and promoters of calcium action in the excitation-contraction coupling of heart muscle and their role in the prevention or production of myocardial lesions, in Calcium and the Heart, P. Harris and L. Opie, eds., pp. 135–188, Academic, London, 1971.

    Google Scholar 

  • Fleckenstein, A.: Specific pharmacology of calcium in myocardium, cardiac pacemakers, and vascular smooth muscle. Annu. Rev. Pharmacol Toxicol. 17:149–166, 1977.

    Article  PubMed  CAS  Google Scholar 

  • Fleckenstein, A.: Calcium Antagonism in Heart and Smooth Muscle: Experimental Facts and Therapeutic Prospects. Wiley, New York, 1983.

    Google Scholar 

  • Fleckenstein, A.: Calcium antagonism: History and prospects for a mul-tifaceted pharmacodynamic principle, in Calcium Antagonists and Cardiovascular Disease, L. H. Opie, ed., pp. 9–28, Raven, New York, 1984.

    Google Scholar 

  • Fleckenstein, A. and Roskamm, H.: Calcium-Antagonismus. Springer-Verlag, Berlin, 1980.

    Book  Google Scholar 

  • Fleckenstein, A., Kammermeier, H., Döring, H. J., and Freund, H. J.: Zum Wirkungsmechanismus neuartiger Koronardilatatoren mit gleichzeitig Sauerstoff-einsparendenMyokard-Effekten,PrenylaminundIproveratril. Kreislaufforsch 56: part 1,716–744; part 2,839-858, 1967.

    CAS  Google Scholar 

  • Fleckenstein, A., Tritthart, H., Döring, H. J., and Byon, K. Y.: Bay a 1040—ein hochaktiver Ca++-antagonistischer Inhibitor der elektro-mechanischen Koppelungsprozesse im Warmblütter-Myokard. Arzneimittelforsch. 22: 22–33, 1972.

    PubMed  CAS  Google Scholar 

  • Fleckenstein, A., Tritthart, H., Fleckenstein, B., Herbst, A., and Grün, G.: A new group of competitive Ca-antagonists (Iproveratril, D600, Prenyla-mine) with highly potent inhibitory effects on excitation-contraction coupling in mammalian myocardium. Pflugers Arch. 307: R25, 1969.

    PubMed  CAS  Google Scholar 

  • Frishman, W. H., Charlap, S., and Michelson, E. L.: Calcium channel blockers in systemic hypertension. Am. J. Cardiol. 58:157–160, 1986.

    Article  PubMed  CAS  Google Scholar 

  • Grün, G. and Heckenstein, A.: Die elektromechanische Entkoppelung der glatten Gef ässmuskulatur als Grundprinzip der Coronardilatation durch 4-(2′-Nitrophenyl)-2,6-dimethyl-1,4,dihydropyridin-3,5-dicarbonsäure-dimethyl-ester (Bay a 1040, Nifedipine). Arzneimittelforsch. 22: 334–344, 1972.

    PubMed  Google Scholar 

  • Haas, H. and Härtfelder, G.: α-Isopropyl-α-[(N-methyl-N-homoveratryl)-γ-amino-propyl]-3,4-dirnethoxyphenylacetonitril, eine Substanz mit coro-nargefässerweiternden Eigenschaften. Arzneimittelforsch. 12: 549–558, 1962.

    PubMed  CAS  Google Scholar 

  • Halperin, A. K. and Cubeddu, L. X.: The role of calcium channel blockers in the treatment of hypertension. Am. Heart J. 111: 363–382, 1986.

    Article  PubMed  CAS  Google Scholar 

  • Hayase, S., Hirakawa, S., Hosokawa, S., Mori, N., Ito, H., Kondo, Y., Hiei, K., and Banno, S.: Basic and clinical studies on Bay a 1040 with special reference to its influence on the coronary, systemic resistance and capacitance blood vessels. Jpn. Cire. J. 35: 903–914, 1971.

    Article  CAS  Google Scholar 

  • Henry, P. D.: Comparative pharmacology of calcium antagonists: Nifedipine, verapamil and diltiazem. Am. J. Cardiol. 46:1047–1058, 1980.

    Article  PubMed  CAS  Google Scholar 

  • Henry, P. D.: Mechanisms of action of calcium antagonists in cardiac and smooth muscle, in Calcium Channel Blocking Agents in the Treatment of Cardiovascular Disorders, P. H. Stone and E. M. Antman, eds., pp. 107–154, Futura, Mount Kisco,NY, 1983.

    Google Scholar 

  • Hofbauer, K.: Zur Behandlung stenokardischer Beschwerden mit Iproveratril. WienMed. Wochenschr. 116:1155,1156,1966.

    PubMed  CAS  Google Scholar 

  • Hoffmann, P.: Behandlung koronarer Durchblutungsstörungen mit Isoptin in der Praxis. Mediz. Klin. 59:1387–1391, 1964.

    CAS  Google Scholar 

  • Hosada, S. and Kimura, E.: Efficacy of nifedipine in the variant form of angina pectoris, in 3rd International Adalat” Symposium: New Therapy of Ischémie Heart Disease, A. D. Jatene and P. R. Lichtlen, eds., pp. 195–199, Excerpta Medica, Amsterdam, 1976.

    Google Scholar 

  • Janis, R. A., Silver, P. J., and Triggle, D. J.: Drug action and cellular calcium regulation. Adv. Drug Res. 16:309–591, 1987.

    CAS  Google Scholar 

  • Karlsberg, R. P.: Calcium channel blockers for cardiovascular disorders. Arch. Intern. Med. 142:452–455, 1982.

    Article  PubMed  CAS  Google Scholar 

  • Kass, R. S.: Nisoldipine: A new, more selective calcium current blocker in cardiac Purkinje fibers. J. Pharmacol. Exp. Ther. 223:446–456, 1982.

    PubMed  CAS  Google Scholar 

  • Kazda, S., Garthoff, B., Meyer, H., Schlossmann, K., Stoepel, K., Towart, R., Vater, W., and Wehinger, E.: Pharmacology of a new calcium antagonistic compound, isobutyl methyl l,4-dihydro-2,6-dimethyl-4-(2-nitro-phenyl)-3,5-pyridinedicarboxylate (nisoldipine, Bay k 5552) Arzneimittelforsch. 30:2144–2162, 1980.

    PubMed  CAS  Google Scholar 

  • Kendall, M. J. and Okopski, J. V.: Calcium antagonism—with special reference to diltiazem. J. Clin. Hosp. Pharm. 11:159–174, 1986.

    PubMed  CAS  Google Scholar 

  • Kimura, E., moderator: Panel discussion on the variant form of angina pectoris. Jpn. Cire. J. 42:455–76, 1978.

    Article  CAS  Google Scholar 

  • Kimura, E., Mabuchi, G., and Kikuchi, H.: The clinical effect of 4-(2′-nitro-phenyl)-2,6-dimethyl-3-5-dicarbomethoxy-l,4-dihydropyridine (Bay a 1040) on angina pectoris evaluated by sequential analysis. Arzneimittelforsch. 22:365–367, 1972.

    PubMed  CAS  Google Scholar 

  • Kobayashi, T., Ito, Y., and Tawara, I.: Clinical experience with a new coronary-active substance (Bay a 1040). Arzneimittelforsch. 22:380–389, 1972.

    PubMed  CAS  Google Scholar 

  • Kohlhardt, M., Bauer, B., Krause, H., and Fleckenstein, A.: Differentiation of the transmembrane Na and Ca channels in mammalian cardiac fibres by the use of specific inhibitors. Pflugers Arch. 335: 309–322, 1972.

    Article  PubMed  CAS  Google Scholar 

  • Krebs, R.: Calcium antagonists: New vistas in theoretical basis and clinical use, in Calcium Antagonists and Cardiovascular Disease, L. H. Opie, ed., pp. 347–357, Raven, New York, 1984.

    Google Scholar 

  • Krikler, D.M.: Calcium antagonists for chronic stable angina pectoris. Am. J. Cardiol. 59:95B–100B, 1987.

    Article  PubMed  CAS  Google Scholar 

  • Kroneberg, G.: Angina and myocardial infarction—introduction, in Calcium Antagonists and Cardiovascular Disease, L. H. Opie, ed., pp. 205–207, Raven, New York, 1984.

    Google Scholar 

  • Larach, D. R. and Zelis, R.: Advances in calcium blocker therapy. Am. J. Surgery 151:527–537, 1986.

    Article  CAS  Google Scholar 

  • Lichtlen, P. R., ed.: 6th International Adalat® Symposium: New Therapy of Ischaemic Heart Disease and Hypertension, Excerpta Medica, Amsterdam, 1986.

    Google Scholar 

  • Loos, A. and Kaltenbach, M.: Die Wirkung von Nifedipine (Bay a 1040) auf das Belastungs-Elektrokardiogramm von Angina pectoris-Kranken. Arzneimittelforsch. 22:358–362, 1972.

    PubMed  CAS  Google Scholar 

  • Luebs, E. D., Cohen, A., Zaleski, E. J., and Bing, R. J.: Effect of nitroglycerin, intensain, isoptin and papaverine on coronary blood flow in man. Am. J. Cardiol. 17:535–541, 1966.

    Article  PubMed  CAS  Google Scholar 

  • Melville, K. I. and Benfey, B. G.: Coronary vasodilatory and cardiac ad-renergic blocking effects of iproveratril. Can. J. Physiol. Pharmacol. 43: 339–342, 1965.

    Article  PubMed  CAS  Google Scholar 

  • Melville, K. I., Shister, H. E., and Huq, S.: Iproveratril: Experimental data on coronary dilatation and antiarrhythmic action. Can. Med. Assoc. J. 90: 761–770, 1964.

    PubMed  CAS  Google Scholar 

  • Mignault, J. de L.: Coronary cineangiographic study of intravenously administered isoptin. Can. Med. Assoc. J. 95:1252,1253,1966.

    PubMed  CAS  Google Scholar 

  • Mizuno, Y., Yasui, S., Sotohata, I., Nakagawa, K., Hashimoto, Y., Nagaya, A., Nonokawa, A., Horiba, Y., Aihara, N., Tsuchiya, T., Ishikawa, K., Ooishi, H., Uchiyama, O., Kuwuhara, M., and Kashiwagi, C: Effect of CRD-401 on ischémie heart disease. Jpn.J. Clin. Exp. Med. 50:565–573, (in Japanese), 1973.

    Google Scholar 

  • Nakajima, H., Hoshiyama, M., Yamashita, K., and Kiyomoto, A.: Effect of diltiazem on electrical and mechanical activity of isolated cardiac ventricular muscle of guinea pig. Jpn. J. Pharmacol. 25:383–392, 1975.

    Article  PubMed  CAS  Google Scholar 

  • Needleman, P., Corr, P. B., and Johnson, E. M., Jr.: Drugs used for the treatment of angina: Organic nitrates, calcium channel blockers, and beta-adrenergic antagonists, in The Pharmacological Basis of Therapeutics, 7th Ed., A. G. Gilman, L. S. Goodman, T. W. Rail, and F. Murad, eds., pp. 806–826, Macmillan, New York, 1985.

    Google Scholar 

  • Neumann, M. and Luisada, A. A.: Double blind evaluation of orally administered iproveratril in patients with angina pectoris. Am. J. Med. Sci. 251:552–556, 1966.

    Article  PubMed  CAS  Google Scholar 

  • Opie, L. H.: Calcium, calcium ions, and cardiovascular disease, in Calcium Antagonists and Cardiovascular Disease, L. H. Opie, ed., pp. 1–8, Raven, New York, 1984a.

    Google Scholar 

  • Opie, L. H., ed.: Calcium Antagonists and Cardiovascular Disease, Raven, New York, 1984b.

    Google Scholar 

  • Opie, L. H. and Singh, B. N.: Calcium channel antagonists (slow channel blockers) in Drugs for the Heart, 2nd Ed., pp. 34–53, Grune and Stratton, Orlando,FL, 1987.

    Google Scholar 

  • Oyama, Y., Akutsu, Y., Tsushima, N., and Iwamoto, M.: Clinical experience with CRD-401 in angina pectoris. Jpn. J. Clin. Exp. Med. 49:1954–1957, (in Japanese), 1972.

    Google Scholar 

  • Reuter, H.: The dependence of slow inward current in Purkinje fibres on the extracellular calcium-concentration. J. Physiol. 192: 479–492, 1967.

    PubMed  CAS  Google Scholar 

  • Reuter, H. and Beeler, G. W., Jr.: Calcium current and activation of contraction in ventricular myocardial fibers. Science 163: 399–401, 1969.

    Article  PubMed  CAS  Google Scholar 

  • Sandier, G., Clayton, G. A., and Thornicroft, S. G.: Clinical evaluation of verapamil in angina pectoris. Br. Med. J. 3:224–227, 1968.

    Article  Google Scholar 

  • Sato, M., Nagao, T., Yamaguchi, I., Nakajima, H., and Kiyomoto, A.: Pharmacological studies on a new 1,5-benzothiazepine derivative (CRD-401). Arzneimittelforsch. 21:1338–1343, 1971.

    PubMed  CAS  Google Scholar 

  • Schneck, D.W.: Calcium-entry blockers: A review of their basic and clinical pharmacology and therapeutic applications. Ration. Drug Ther. 19:1–6, 1985.

    PubMed  CAS  Google Scholar 

  • Scriabine, A.: Current and potential indications for Ca2+antagonists. Ration. Drug Ther. 21:1–6, 1987.

    PubMed  CAS  Google Scholar 

  • Singh, B. N., Ellrodt, G., and Peter, C.T.: Verapamil: A review of its pharmacological properties and therapeutic use. Drugs 15:169–197, 1978.

    Article  PubMed  Google Scholar 

  • Spivack, C., Ocken, S., and Frishman, W. H.: Calcium antagonists. Clinical use in the treatment of systemic hypertension. Drugs 25:154–177, 1983.

    Article  PubMed  CAS  Google Scholar 

  • Stone, P. H., Antman, E. M., Müller, J. E., and Braunwald, E.: Calcium channel blocking agents in the treatment of cardiovascular disorders. Part 2: Hemodynamic effects and clinical applications. Ann. Intern. Med. 93: 886–904, 1980.

    PubMed  CAS  Google Scholar 

  • Towart, R.: The selective inhibition of serotonin-induced contractions of rabbit cerebral vascular smooth muscle by calcium-antagonistic dihy-dropyridines. Circ. Res. 48:650–657, 1981.

    Article  PubMed  CAS  Google Scholar 

  • Tschirdewahn, B. and Klepzig, H.: Klinische Untersuchung über die Wirkung von Isoptin und Isoptin S bei Patienten mit Koronarinsuffizienz. Dtsch. Med. Wochenschr. 88:1702–1707, 1963.

    Article  PubMed  CAS  Google Scholar 

  • Urthaler, F.: Review: Role of calcium channel blockers in clinical medicine. Am. J. Med. Sci. 292:217–230, 1986.

    Article  PubMed  CAS  Google Scholar 

  • Vater, W., Kroneburg, G., Hoffmeister, F., Kailer, H., Meng, K., Oberdorf, A., Puls, W., Schlossman, K., and Stoepel, K.: Zur Pharmakologie von 4-(2′-Nitrophenyl)-2,6-dimethyl-l, 4-dihydropyridin-3,5-dicarbonsäure-dimethylester (Nifedipine, Bay a 1040). Arzneimittelforsch. 22:1–14, 1972.

    PubMed  CAS  Google Scholar 

  • Winbury, M. M.: Antianginal drugs, in Discoveries in Pharmacology, vol. 2, Haemodynamics, Hormones and Inflammation, M. J. Parnham and J. Bruin-vels, eds., pp. 141–161, Elsevier, Amsterdam 1984.

    Google Scholar 

  • Yasue, H., Nagao, M., Orote, S., Takizawa, A., Miwa, K., and Tanaka, S.: Coronary arterial spasm and Prinzmetal’s variant form of angina induced by hyperventilation and tris-buffer infusion. Circulation 58:56–62, 1978a.

    Article  PubMed  CAS  Google Scholar 

  • Yasue, H., Omote, S., Takizawa, A., Nagao, M., Miwa, K., Kato, H., Tanaka, S., and Akiyama, F.: Pathogenesis and treatment of angina pectoris at rest as seen from its response to various drugs. Jpn. Circ. J., 42:1–10, 1978b.

    Article  PubMed  CAS  Google Scholar 

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  1. The Wellcome Research Laboratories Research, Triangle Park, North Carolina, USA

    Robert A. Maxwell

  2. University of Vermont College of Medicine, Burlington, Vermont, USA

    Shohreh B. Eckhardt

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Maxwell, R.A., Eckhardt, S.B. (1990). Calcium Antagonists. In: Drug Discovery. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-4612-0469-5_3

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  • DOI: https://doi.org/10.1007/978-1-4612-0469-5_3

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