Skip to main content
SpringerLink
Log in

Calcium Ion Channels and Their Blockers

  • Chapter
  • First Online:
Ion Channels and Their Inhibitors

  • 1249 Accesses

Abstract

Calcium is a ubiquitous second messenger. Calcium entry into the cytosol is mediated by multiple types of calcium channels each with a distinct physiological role. There exist five different types of voltage-dependent Ca2+ channel. The calcium ion channel blocking agents are a chemically, pharmacologically, and therapeutically heterogeneous group of drugs. Most calcium channel blockers decrease the force of contraction of the myocardium resulting in a decrease in blood pressure. Representative classes include: (a) dihydropyridines and (b) nondihydropyridines. Structure–activity relationship studies and the structural features that are characterized as prerequisite for the calcium ion channel-blocking activity indicate that the presence of a C-4 phenyl group is a preferential requirement to optimize the biological activity. Steric hindrance is shown to be significant. No relationship of activity is indicated with electronic or lipophilic properties.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

DHPs:

Dihydropyridines

HVA:

High-voltage-activated

LCC:

L-type Ca2+ ion channels

LSSVM:

Least squares support vector machine

QSAR:

Quantitative SAR structure–activity relationships

QTMS:

Quantum topological molecular similarity

SAR:

Structure–activity relationships

VDCCs:

Voltage-dependent calcium channels

References

  1. Zamponi GW (1998) Antagonist binding sites of voltage-dependent calcium channels. Drug Dev Res 42:131–143

    Google Scholar 

  2. Catterall WA (1994) Molecular properties of a superfamily of plasma-membrane cation channels. Curr Opin Cell Biol 6:607–615

    CAS  Google Scholar 

  3. Walker D, De Waard M (1998) Subunit interaction sites in voltage-dependent Ca2+ channels: role in channel function. Trends Neurosci 21(4):148–154

    CAS  Google Scholar 

  4. Fatt P, Katz B (1953) The electrical properties of crustacean muscle fibres. J Physiol 120:171–204

    CAS  Google Scholar 

  5. Fatt P, Ginsborg BL (1958) The ionic requirements for the production of action potentials in crustacean muscle fibres. J Physiol 142:516–543

    CAS  Google Scholar 

  6. Hagiwara S, Byerly L (1981) Calcium channel. Annu Rev Neurosci 4:69–125

    CAS  Google Scholar 

  7. Dolphin AC (2006) A short history of voltage-gated calcium channels. Br J Pharmacol 147(suppl 1):S56–S62

    CAS  Google Scholar 

  8. Barton ME, Eberle EL, Shannon HE (2005) The antihyperalgesic effects of the T-type calcium channel blockers ethosuximide, trimethadione, and mibefradil. Eur J Pharmacol 521:79–85

    CAS  Google Scholar 

  9. Coulter DA, Huguenard JR, Prince DA (1989) Calcium currents in rat thalamocortical relay neurons: kinetic properties of the transient, low-threshold current. Ann Neurol 25:582–593

    CAS  Google Scholar 

  10. Coulter DA, Huguenard JR, Prince DA (1990) Differential effects of petit mal anticonvulsants and convulsants on thalamic neurones: GABA current blockade. Br J Pharmacol 100:800–806

    CAS  Google Scholar 

  11. Nelson MT, Todorovic SM (2006) The role of T-type calcium channels in epilepsy and pain. Curr Pharm Des 12:2189–2197

    CAS  Google Scholar 

  12. Perez-Reyes E (2003) Molecular physiology of low-voltage-activated T-type calcium channels. Physiol Rev 83:117–161

    CAS  Google Scholar 

  13. Catterall WA, Perez-Reyes E, Snutch TP, Striessnig J (2005) International union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels. Pharmacol Rev 57:411–425

    CAS  Google Scholar 

  14. McRory JE, Santi CM, Hamming KSC, Mezeyova J, Sutton KG, Baillie DL, Stea A, Snutch TP (2001) Molecular and functional characterization of a family of rat brain T-type calcium channels. J Biol Chem 276:3999–4011

    CAS  Google Scholar 

  15. Shin H-S, Cheong E-J, Choi S, Lee J, Na HS (2008) T-type Ca2+ channels as therapeutic targets in the nervous system. Curr Opin Pharmacol 8:33–41

    CAS  Google Scholar 

  16. Ertel EA, Campbell KP, Harpold MM, Hofmann F, Mori Y, Perez-Reyes E, Schwartz A, Snutch TP, Tanabe BL, Tsien RW, Catterall WA (2000) Nomenclature of voltage-gated calcium channels. Neuron 25:533–535

    CAS  Google Scholar 

  17. Doering D, Zamponi G, Connolly TM, Barrow JC, Triggle DJ, Snutch TP (2006) Voltage-gated ion channels as drug targets. Wiley-VCH, Weinhiem

    Google Scholar 

  18. McDonough SI, Bean BP (1998) Mibefradil inhibition of T-type calcium channels in cerebellar Purkinje neurons. Mol Pharmacol 54:1080–1087

    CAS  Google Scholar 

  19. Mishra SK, Hermsmeyer K (1994) Selective inhibition of T-type Ca2+ channels by Ro 40–5967. Circ Res 75:144–148

    CAS  Google Scholar 

  20. SoRelle R (1998) Withdrawal of Posicor from market. Circulation 98:831–832

    CAS  Google Scholar 

  21. Flatters SJL (2005) T-type calcium channels: a potential target for the treatment of chronic pain. Drugs Future 30:573–580

    CAS  Google Scholar 

  22. Hoth M (1995) Calcium and barium permeation through calcium release-activated calcium (CRAC) channels. Pflugers Arch 430(3):315–322

    CAS  Google Scholar 

  23. Hoth M, Penner R (1992) Depletion of intracellular calcium stores activates a calcium current in mast cells. Nature 355:353–356

    CAS  Google Scholar 

  24. Lewis RS, Cahalan MD (1995) Potassium and calcium channels in lymphocytes. Annu Rev Immunol 13:623–653

    CAS  Google Scholar 

  25. Clementi E, Meldolesi J (1996) Pharmacological and functional properties of voltagemi independent Ca2+ channels. Cell Calcium 19:269–279

    CAS  Google Scholar 

  26. Geiszt M, Kapus A, Nemet K, Farkas L, Ligeti E (1997) Regulation of capacitative Ca2+ influx in human neutrophil granulocytes. Alterations in chronic granulomatous disease. J Biol Chem 272:26471–26478

    CAS  Google Scholar 

  27. Clapham DE (1995) Calcium signaling. Cell 80:259–268

    CAS  Google Scholar 

  28. Gray LS, Perez-Reyes E, Gamorra JC, Haverstick DM, Shattock M, McLatchie L, Harper J, Brooks G, Heady T, Macdonald TL (2004) The role of voltage gated T-type Ca2+ channel isoforms in mediating “capacitative” Ca2+ entry in cancer cells. Cell Calcium 36(6):489–497

    CAS  Google Scholar 

  29. Portegies MC, Schmitt R, Kraaij CJ, Braat SHJG, Gassner A, Hagemeijer F, Ponzenel H, Prager G, Viersma JW, VanderWall EE, Kleinbloesem CH, Lie KI (1991) Lack of negative inotropic effects of the new calcium antagonist Ro 40–5967 in patients with stable angina pectoris. J Cardiovasc Pharmacol 18:746–751

    CAS  Google Scholar 

  30. Cremers B, Flesch M, Sudkamp M, Bohm M (1997) Effects of the novel T-type calcium channel antagonist mibefradil on human myocardial contractility in comparison with nifedipine and verapamil. J Cardiovasc Pharmacol 29:692–696

    CAS  Google Scholar 

  31. Sheng ZH, Rettig J, Cook T, Catterall WA (1996) Calcium-dependent interaction of N-type calcium channels with the synaptic core complex. Nature 379:451–454

    CAS  Google Scholar 

  32. Saegusa H, Kurihara T, Zong S, KazunoA MY, Nonaka T, Han W, Toriyama H, Tanabe T (2001) Suppression of inflammatory and neuropathic pain symptoms in mice lacking the N-type Ca2+ channel. EMBO J 20:2349–2356

    CAS  Google Scholar 

  33. Cox B, Denyer J (1998) Patents N-type calcium channel blockers in pain and stroke. Expert Opin Ther Pat 8:1237–1250

    CAS  Google Scholar 

  34. Munikumar RD, Hee KJ, Joo HC, Yong SC, Hun YK, Moon HC, Ae NP (2004) 3D QSAR studies on T-type calcium channel blockers using CoMFA and CoMSIA. Bioorg Med Chem 12:1613–1621

    Google Scholar 

  35. Catterall WA, Striessnig J (1992) Receptor sites for Ca2+ channel antagonists. Trends Pharmacol Sci 13:256–262

    CAS  Google Scholar 

  36. Opie LH, Frishman WH, Thadani U (1999) Calcium channel antagonists (calcium entry blockers). In: Opie LH (ed) Drugs for the heart, 4th edn. Saunders WB, Philadelphia

    Google Scholar 

  37. Abernethy DR, Schwartz JB (1999) Calcium-antagonist drugs. N Engl J Med 341:1447–1457

    CAS  Google Scholar 

  38. Thadani U (1999) Management of stable angina pectoris. Curr Opin Cardiol 14:349–358

    CAS  Google Scholar 

  39. Glossmann H, Ferry DR, Goll A, Striessnig J, Zernig G (1985) Calcium channels and calcium channel drugs: recent biochemical and biophysical findings. Arzneimittelforschung 35:1917–1935

    CAS  Google Scholar 

  40. Höltje H-D, Marrer S (1987) A molecular graphics study on structure-action relationships of calcium-antagonistic and agonistic 1,4-dihydropyridines. J Comput Aided Mol Des 1:23–30

    Google Scholar 

  41. Matowe WC, Akula M, Knaus EE, Wolowyk MW (1989) AK-2–38, a nifedipine analogue with potent smooth muscle calcium antagonist action and partial agonist effects on isolated guinea pig left atrium. Proc West Pharmacol Soc 32:305–307

    CAS  Google Scholar 

  42. Vo D, Nguyen JT, McEwen CA, Shan R, Knaus EE (2002) Syntheses, calcium channel agonist-antagonist modulation effects, and nitric oxide release studies of [3-(benzenesulfonyl)furoxan-4-yloxy]alkyl 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-trifluoromethylphenyl, benzofurazan-4-yl, 2-, 3-, or 4-pyridyl)-3-pyridinecarboxylates. Drug Dev Res 56:1–16

    CAS  Google Scholar 

  43. Vo D, Matowe WC, Ramesh M, Iqbal N, Wolowyk MW, Howlett SE, Knaus EE (1995) Syntheses, calcium channel agonist-antagonist modulation activities, and voltage-clamp studies of isopropyl 1, 4-dihydro-2,6-dimethyl-3-nitro-4-pyridinylpyridine-5-carboxylate racemates and enantiomers. J Med Chem 38:2851–2859

    CAS  Google Scholar 

  44. Vo D, Wolowyk MW, Knaus EE (1992) Synthesis and cardioselective beta-adrenergic antagonist activity of quinolyloxypropanolamines. Drug Des Discov 9:69–78

    CAS  Google Scholar 

  45. Coburn RA, Wierzba M, Suto MJ, Solo AJ, Triggle AM, Triggle DJ (1988) 1,4-Dihydropyridine antagonist activities at the calcium channel: a quantitative structure–activity relationship approach. J Med Chem 31:2103–2107

    CAS  Google Scholar 

  46. Safak C, Simsek R (2006) Fused 1,4-dihydropyridines as potential calcium modulatory compounds. Mini Rev Med Chem 6:747–755

    CAS  Google Scholar 

  47. Rose U, Drager M (1992) Synthesis, configuration, and calcium modulatory properties of enantiomerically pure 5-oxo-1, 4, 5, 6, 7, 8-hexahydroquinoline-3-carboxylates. J Med Chem 35:2238–2243

    CAS  Google Scholar 

  48. Miri R, Javidnia K, Sarkarzadeh H, Hemmateenejad B (2006) Synthesis, study of 3D structures, and pharmacological activities of lipophilic nitroimidazolyl-1,4-dihydropyridines as calcium channel antagonist. Bioorg Med Chem 14:4842–4849

    CAS  Google Scholar 

  49. Miri R, Niknahad H, Vazin A, Azarpira A, Shafiee A (2002) Synthesis and smooth muscle calcium channel antagonist effects of new derivatives of 1,4-dihydropyridine containing nitroimidzolyl substituent. DARU 10:130–136

    CAS  Google Scholar 

  50. Miri R, Niknahad H, Vesal G, Shafiee A (2002) Synthesis and calcium channel antagonist activities of 3-nitrooxyalkyl, 5-alkyl1,4-dihydro-2,6-dimethyl-4-(1-methyl-5-nitro-2-imidazolyl)-3,5-pyridinedicaboxylates. Farmaco 57:123–128

    CAS  Google Scholar 

  51. Shafiee A, Miri R, Dehpour AR, Solimani F (1996) Syntheses and calcium channel antagonist activity of nifedipine containing imidazolyl substitutent. Pharm Sci 2:541–543

    CAS  Google Scholar 

  52. Miri R, Javidnia K, Kebriaie-Zadeh A, Niknahad H, Shaygani N, Semnanian S, Shafiee A (2003) Synthesis and evaluation of pharmacological activities of 3,4-dialkyl1,4-dihydro-2,6-dimethyl- 4-nitroimidazole-3,5-pyridine dicarboxylates. Arch Pharm Pharm Med Chem 336:422–428

    CAS  Google Scholar 

  53. Miri R, Javidnia K, Mirkhani H, Hemmateenejad B, Sepeher Z, Zalpour M, Behzad T, Khoshneviszadeh M, Edraki N, Mehdipour AR (2007) Synthesis, QSAR and calcium channel modulator activity of new hexahydroquinoline derivatives containing nitroimidazole. Chem Biol Drug Des 70:329–336

    CAS  Google Scholar 

  54. Goldmann S, Stoltefuss J (1991) 1, 4-Dihydropyridines: effects of chirality and conformation on the calcium antagonist and agonist activities. Angew Chem Int Ed 30:1559–1578

    Google Scholar 

  55. Jauk B, Pernat T, Kappe CO (2000) Design and synthesis of a conformationally rigid mimic of the dihydropyrimidine calcium channel modulator SQ 32,926. Molecules 5:227–239

    CAS  Google Scholar 

  56. Atwal KS, Rovnyak GC, Schwartz J, Morelan S, Hedberg A, Gougoutas JZ, Malley MF, Floyd DM (1990) Dihydropyrimidine calcium channel blockers: 2-heterosubstituted 4-aryl-1,4-dihydro-6- methyl-5-pyrimidinecarboxylic acid esters as potent mimics of dihydropyridines. J Med Chem 33:1510–1515

    CAS  Google Scholar 

  57. Atwal KS, Rovnyak GC, Kimball SD, Floyd DM, Moreland S, Swanson BN, Gougoutas JZ, Schwartz J, Smillie KM, Malley MF (1990) Dihydropyrimidine calcium channel blockers. II. 3- Substituted-4-aryl-1, 4-dihydro-6-methyl-5-pyrimidinecarboxylic acid esters as potent mimics of dihydropyridines. J Med Chem 33:2629–2635

    CAS  Google Scholar 

  58. Atwal KS, Swanson BN, Unger SE, Floyd DM, Moreland S, Hedberg A, O’Reilly BC (1991) Dihydropyrimidine calcium channel blockers. 3. 3-carbamoyl-4-aryl-1,2,3,4-tetrahydro-6-methyl- 5-pyrimidinecarboxylic acid esters as orally effective antihypertensive agents. J Med Chem 34:806–811

    CAS  Google Scholar 

  59. Rovnyak GC, Atwal KS, Hedberg A, Kimball SD, Moreland S, Gougoutas JZ, O’Reilly BC, Schwartz J, Malley MF (1992) Dihydropyrimidine calcium channel blockers. 4. Basic 3-substituted-4-aryl-1, 4-dihydropyrimidine-5-carboxylic acid esters. Potent antihypertensive agents. J Med Chem 35:3254–3263

    CAS  Google Scholar 

  60. Gupta SP, Veerman A, Bagar P (2000) Quantitative structure–activity relationship studies on some series of calcium channel blockers. Mol Divers 8:357–363

    Google Scholar 

  61. Harrold M (2002) Angiotensin converting enzyme inhibitors, antagonist and calcium channel blockers. In: Lemke TL, Williams D (eds) Foye’s principles of medicinal chemistry. Lippincott Williams & Wilkins, Baltimore, MD

    Google Scholar 

  62. Mohajeri A, Hemmateenejad B, Mehdipour A, Miri R (2008) Modeling calcium channel antagonistic activity of dihydropyridine derivatives using QTMS indices analyzed by GA-PLS and PC-GAPLS. J Mol Graph Model 26:1057–1065

    CAS  Google Scholar 

  63. Mojarrad JS, Miri R, Knaus EE (2004) Design and synthesis of methyl 2-methyl-7, 7-dihalo-5- phenyl-2-azabicyclo [4.1.0] hept-3-ene-4-carboxylates with calcium channel antagonist activity. Bioorg Med Chem 12:3215–3220

    CAS  Google Scholar 

  64. Dagnino L, Li-Kwong-Ken MC, Wolowyk MC, Wynn H, Triggle CR, Knaus EE (1986) Synthesis and calcium channel antagonist activity of dialkyl 1,4-dihydro-2,6-dimethyl-4-(pyridinyl)-3,5- pyridinedicarboxylates. J Med Chem 29:2524–2529

    CAS  Google Scholar 

  65. Hemmateenejad B, Miri R, Safarpour MA, Khoshneviszadeh M, Edraki N (2005) Conformational analysis of some new derivatives of 4-nitroimidazolyl-1,4-dihydropyridine-based calcium channel blockers. J Mol Struct Theochem 717:139–152

    CAS  Google Scholar 

  66. Mahmoudian M, Richards W (1986) A conformational distinction between dihydropyridine calcium agonists and antagonists. J Chem Soc Chem Commun 10:739–741

    Google Scholar 

  67. Handrock R, Herzig S (1996) Stereoselectivity of Ca2+ channel block by dihydropyridines: no modulation by the voltage protocol. Eur J Pharmacol 309:317–321

    CAS  Google Scholar 

  68. Rovnyak GC, Kimball SD, Beyer B, Cucinotta G, DiMarco JD, Gougoutas J, Hedberg A, Malley M, McCarthy JP (1995) Calcium entry blockers and activators: conformational and structural determinants of dihydropyrimidine calcium channel modulators. J Med Chem 38:119–129

    CAS  Google Scholar 

  69. Hemmateenejad B, Safarpour MA, Miri R, Taghavi F (2004) Application of ab initio theory to QSAR study of 1,4-dihydropyridine-based calcium channel blockers using GA-MLR and PC-GA-ANN procedures. J Comput Chem 25:1495–1503

    CAS  Google Scholar 

  70. Mahmoudian M, Richards WGA (1990) Quantum chemical study of structure–activity relationships of dihydropyridine calcium antagonists. J Sci Technol IR Iran 1:261–265

    CAS  Google Scholar 

  71. Gaudio AC, Korolkovas A, Takahata Y (1994) Quantitative structure–activity relationships for 1, 4 -dihydropyridine calcium channel antagonists (nifedipine analogues): a quantum chemical/classical approach. J Pharm Sci 83:1110–1115

    CAS  Google Scholar 

  72. Berntsson P, Wold S (1986) Comparison between X-ray crystallographic data and physicochemical parameters with respect to their information about the calcium channel antagonist activity of 4-phenyl-1,4-dihydropyridines. Quant Struct Act Relat 5:45–50

    CAS  Google Scholar 

  73. Hemmateenejad B, Miri R, Akhond M, Shamsipur M (2002) Quantitative structure–activity relationship study of recently synthesized 1, 4-dihydropyridine calcium channel antagonists. Application of the Hansch analysis method. Arch Pharm Weinheim 335:472–480

    CAS  Google Scholar 

  74. Gupta SP, Mathur AN, Nagappa AN, Kumar D, Kumaran S (2003) A quantitative structure–activity relationship study on a novel class of calcium entry blockers:1-[{4-(aminoalkoxy)phephenyl} sulphonyl] Indolizines. Eur J Med Chem 38:867–873

    CAS  Google Scholar 

  75. Miri R, Javidnia K, Hemmateenejad B, Tabarzad M, Jafarpour M (2009) Synthesis, evaluation of pharmacological activities and quantitative structure–activity relationship studies of a novel group of bis(4-nitroaryl-1,4-dihyropyridine). Chem Biol Drug Des 73:225–235

    CAS  Google Scholar 

  76. Hemmateenejad B, Miri R, Akhond M, Shamsipur M (2002) QSAR study of the calcium channel antagonist activity of some recently synthesized dihydropyridine derivatives. An application of genetic algorithm for variable selection in MLR and PLS methods. Chemometr Intell Lab Syst 64:91–99

    CAS  Google Scholar 

  77. Hemmateenejad B, Akhond M, Miri R, Shamsipur M (2003) Genetic algorithm applied to the selection of factors in principal component-artificial neural networks: application to QSAR study of calcium channel antagonist activity of 1,4-dihydropyridines (nifedipine analogous). J Chem Inf Comput Sci 43:1328–1334

    CAS  Google Scholar 

  78. Si HZ, Wang T, Zhang Ke Jun, De Hua Z, Fane Bo Tao (2006) QSAR study of 1, 4-dihydropyridine calcium channel antagonists based on gene expression programming. Bioorg Med Chem 14:4834–4841

    CAS  Google Scholar 

  79. Safarpour MA, Hemmateenejad B, Miri R, Jamali M (2004) Quantum chemical-QSAR study of some newly synthesized 1,4-dihydropyridine calcium channel blockers. QSAR Comb Sci 22:997–1005

    CAS  Google Scholar 

  80. Yao X, Liu H, Zhang R, Liu M, Hu Z (2005) QSAR and classification study of 1,4-dihydropyridine calcium channel antagonists based on least squares support vector machines. Mol Pharm 2:348–356

    CAS  Google Scholar 

  81. Costa MCA, Gaudio AC, Takahata Y (1997) A comparative study of principal component and linear multiple regression analysis in SAR and QSAR applied to 1,4-dihydropyridine calcium channel antagonists (nifedipine analogues). J Mol Struct Theochem 394:291–300

    CAS  Google Scholar 

  82. Schleifer KJ, Tot E (2002) CoMFA, CoMSIA and GRID/GOLPE studies on calcium entry blocking 1,4-dihydropyridines. Quant Struct Act Rel 21:239–248

    CAS  Google Scholar 

  83. Kawada T, Hsiao-Tung S, Nakazawa M, Imai S (2000) In vitro effects of the new calcium antagonist lacidipine. Jpn J Pharmacol 62:289–296

    Google Scholar 

  84. Van Amsterdam FTM, Roveri A, Maiorino M, Ratti E, Ursini F (1992) Lacidipine: a dihydropyridine calcium antagonist with antioxidant activity. Free Redic Biol Med 12:183–187

    Google Scholar 

  85. Lupo E, Locher R, Weisser B, Vetter W (1994) In vitro antioxidant activity of calcium antagonists against LDL oxidation compared with α-tocopherol. Biochem Biophys Res Commun 203:1803–1808

    CAS  Google Scholar 

  86. Berkels R, Breitenbach T, Bartels H, Taubert D, Roesenkranz A, Klaus W, Roesen R (2005) Different antioxidative potencies of dihydropyridine calcium channel modulators in various models. Vascul Pharmacol 42:145–152

    CAS  Google Scholar 

  87. Hockerman GH, Peterson BZ, Johnson BD, Catterall WA (1997) Molecular determinants of drug binding and action on L-type calcium channels. Annu Rev Pharmacol Toxicol 37:361–396

    CAS  Google Scholar 

  88. Manhold R, Steiner R, Hass W, Kaufman R (1978) Investigations on the structure–activity relationships of verapamil. Naunyn Schmiedebergs Arch Pharmacol 302:217–226

    Google Scholar 

  89. Triulzi MO, Mattioli R, Signorini G, Cirino D, Esposti D, Aguggini G, Maggi GC (1990) Effects of low-dose diltiazem on isovolumetric relaxation and contraction. G Ital Cardiol 20:1137–1143

    CAS  Google Scholar 

  90. Corelli F, Manetti F, Taft A, Campiani G, Nacci V, Botta M (1997) Diltiazem-like calcium entry blockers: a hypothesis of the receptor-binding site based on a comparative molecular field analysis model. J Med Chem 40:125–131

    CAS  Google Scholar 

  91. Campiani G, Garofalo A, Fiorini I, Botta M, Nacci V, Taft A, Chiarini A, Budriest R, Bruni G, Romeo MR (1995) Pyrrolo[2,1-c][1,4]benzothiazines: synthesis, structure–activity relationships, molecular modeling studies, and cardiovascular activity. J Med Chem 38:4393–4410

    CAS  Google Scholar 

  92. Kimball SD, Floyd DM, Das J, Hunt JT, Krapcho J, Rovnyak G, Duff KJ, Lee VG, Moquin RV, Turk CF, Hedberg SA, Moreland S, Brittain RJ, McMullen DM, Normandin DE, Cucinotta GG (1992) Benzazepinone calcium channel blockers. 4. Structure–activity overview and intracellular binding site. J Med Chem 35:780–793

    CAS  Google Scholar 

  93. Inoue H, Konda M, Hashiyama T, Otsuka H, Takahashi K, Gaino M, Date T, Aoe K, Takeda M, Murata S, Narita H, Nagao T (1991) Synthesis of halogen-substituted 1,5-benzothiazepine derivatives and their vasodilating and hypotensive activities. J Med Chem 34:675–687

    CAS  Google Scholar 

  94. Floyd DM, Kimball SD, Krapcho J, Das J, Turk CF, Moquin RV, Lago MW, Duff KJ, Lee VG, White RE, Ridgewell RE, Moreland S, Brittain RJ, Normandin DE, Hedberg SA, Cucinotta GG (1992) Benzazepinone calcium channel blockers. 2. Structure activity and drug metabolism studies leading to potent antihypertensive agents. Comparison with benzothiazepinones. J Med Chem 35:756–772

    CAS  Google Scholar 

  95. Das J, Floyd DM, Kimball SD, Duff KJ, Vu TC, Lago MW, Moquin RV, Lee VG, Gougoutas JZ, Malley MF, Moreland S, Brittain RJ, Hedberg SA, Cucinotta GG (1992) Benzazepinone calcium channel blockers. 3. Synthesis and structure–activity studies of 3-alkylbenzazepinones. J Med Chem 35:773–780

    CAS  Google Scholar 

  96. Clozel J, Ertel E, Ertel SJ (1997) Discovery and main pharmacological properties of mibefradil (Ro 40–5967), the first selective T-type calcium channel blocker. J Hypertens 15:S17–S25

    CAS  Google Scholar 

  97. Van der Vring J, Cleophas T, Van der Wall E, Niemeyer M (1999) T-channel-selective calcium channel blockade: a promising therapeutic possibility, only preliminarily tested so far: a review of published data. Am J Ther 6:229–233

    Google Scholar 

  98. Benardeau A, Ertel E (1997) Selective block of myocardial T-type calcium channels by mibefradil: A comparison with the 1,4- dihydropyridine amlodipine. Adis International Chester, UK

    Google Scholar 

  99. Ertel SI, Ertel EA, Clozel JP (1997) T-type Ca2+ channels and pharmacological blockade: potential pathophysiological relevance. Cardiovasc Drugs Ther 11:723–739

    CAS  Google Scholar 

  100. Kobrin I, Bieska G, Charlon V, Lindberg E, Pordy R (1998) Anti-anginal and anti-ischemic effects of mibefradil, a new T-typecCalcium channel antagonist. Cardiology 89:23–32

    CAS  Google Scholar 

  101. Asirvatham S, Sebastian C, Thadani U (1998) Choosing the most appropriate treatment for stable angina: safety considerations. Drug Saf 19:23–44

    CAS  Google Scholar 

  102. Jeong JA, Cho H, Yeon Jung S, Kang HB, Park JY, Kim J, Joon DJ, Lee JY (2010) 3D QSAR studies on 3,4-dihydroquinazolines as T-type calcium channel blocker by comparative molecular similarity indices analysis (CoMSIA). Bioorg Med Chem Lett 20:38–41

    CAS  Google Scholar 

  103. Seo HN, Choi JY, Choe YJ, Kim Y, Rhim H, Lee SH, Kim J, Joo DJ, Lee JY (2007) Discovery of potent T-type calcium channel blocker. Bioorg Med Chem Lett 17:5740–5743

    CAS  Google Scholar 

  104. Heo JH, Seo HN, Choe YJ, Kim S, Oh CR, Kim YD, Rhim H, Choo DJ, Kim J, Lee JY (2008) Synthesis and evaluation of α, α′-disubstituted phenylacetate derivatives for T-type calcium channel blockers. Bioorg Med Chem Lett 18:4424–4427

    Google Scholar 

  105. Park JH, Choi JK, Lee E, Lee JK, Rhim H, Seo SH, Kim Y, Doddareddy MR, Pae AN, Kang J, Roh EJ (2007) Lead discovery and optimization of T-type calcium channel blockers. Bioorg Med Chem 15:1409–1419

    CAS  Google Scholar 

  106. Doddareddy MR, Choo H, Cho YS, Rhim H, Koh HY, Lee J-H, Jeong S-W, Pae AN (2007) 3D pharmacophore based virtual screening of T-type calcium channel blockers. Bioorg Med Chem 15:1091–1105

    CAS  Google Scholar 

  107. Jo MN, Seo HJ, Kim Y, Seo SH, Rhim H, Cho YS, Cha JH, Koh HY, Choo H, Pae AN (2007) Novel T-type calcium channel blockers: dioxoquinazoline carboxamide derivatives. Bioorg Med Chem 15:365–373

    CAS  Google Scholar 

  108. Ku IW, Cho S, Doddareddy MR, Jang MS, Keum G, Lee JH, Chung BY, Kim Y, Rhim H, Kang SB (2006) Morpholin-2-one derivatives as novel selective T-type Ca2+ channel blockers. Bioorg Med Chem Lett 16:5244–5248

    CAS  Google Scholar 

  109. Papaioannou S, Panzer-Knodle S, Yang PC (1987) Calcium channel blockers: correlation among receptor binding, calcium uptake and contractility in vitro. J Pharmacol Exp Ther 241:91–96

    CAS  Google Scholar 

  110. Gupta SP (2006) QSAR studies on calcium channel blockers. In: Gupta SP (ed) QSAR and modeling studies in heterocyclic drugs II, 1st edn. Springer, Germany

    Google Scholar 

  111. Gaviraghi G (1989) Lacidipine, a new 1,4-dihydropyridine calcium channel antagonist possessing a potent and long lasting antihypertensive activity. Trends Med Chem 12:675–690

    Google Scholar 

  112. Kimball SD, Hunt JT, Barrish JC, Das J, Floyd DM, Lago MW, Lee VG, Spergel SH, Moreland S, Hedberg SA, Gougoutas JZ, Malley MF, Lau WF (1993) 1-Benzazepin-2-one calcium channel blockers-VI. Receptor-binding model and possible relationship to desmethoxyverapamil. Bioorg Med Chem 1:285–307

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, Thessaloniki, 54124, Greece

    Dimitra Hadjipavlou-Litina

Authors
  1. Dimitra Hadjipavlou-Litina
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dimitra Hadjipavlou-Litina .

Editor information

Editors and Affiliations

  1. , Dept. of Pharmaceutical Technology, Meerut Institute of Engineering and Tech, Baghpat Road Bypass Crossing, Meerut, 250005, India

    Satya Prakash Gupta

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Hadjipavlou-Litina, D. (2011). Calcium Ion Channels and Their Blockers. In: Gupta, S. (eds) Ion Channels and Their Inhibitors. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-19922-6_9

Download citation

Publish with us

Policies and ethics

Search

Navigation