Advertisement

SR 33557, a novel calcium-antagonist: interaction with [3H]-(±)-nitrendipine and [3H]-(−)-desmethoxy-verapamil binding sites in cerebral membranes

  • P. Nokin
  • M. Clinet
  • P. Polster
  • P. Beaufort
  • L. Meysmans
  • J. Gougat
  • P. Chatelain
Article

Summary

We investigated the pharmacological properties of SR 33557, a novel compound with calcium-antagonist properties, in both functional tests in vitro and radioligand binding studies. SR 33557 potently antagonized calcium-induced contraction of potassium-depolarized rat aorta in vitro with an IC50 value of 5.6 ± 0.9 nM, but was a much weaker inhibitor of noradrenaline-induced contraction of the same tissue (IC50 = 96 ± 22 nM). SR 33557 totally inhibited [3H]-(±)-nitrendipine binding to rat brain membranes with a Ki value of 0.19 ± 0.03 nM. Diltiazem, which used alone increases [3H]-(±)-nitrendipine binding, reversed this inhibition indicating that SR 33557 allosterically regulates [3H]-(±)-nitrendipine binding. SR 33557 also fully inhibited [3H]-(−)-desmethoxyverapamil binding to cerebral membranes, but inhibition curves were biphasic. IC50 value calculated for that part of the curve which reflects the high affinity binding site of SR 33557 (IC50 = 0.20 ± 0.02 nM) was very similar to the Ki value determined for inhibition of [3H]-(±)-nitrendipine binding. Kinetic evidences indicate that SR 33557 binds to a site which is distinct from the 1,4-dihydropyridine or the phenylalkylamine binding sites associated with the calcium channel. To test the pharmacological specificity of these interactions, the ability of SR 33557 to interact with eight other receptors in cerebral or heart membranes was assessed by binding assays. No high-affinity interaction was observed between SR 33557 and any of the receptors investigated. We conclude that SR 33557 binds specifically and with a high affinity to a site closely associated with the voltage-operated calcium channel in cerebral membranes.

Key words

Calcium antagonist Depolarization-induced contraction Binding sites SR 33557 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Balwierczak JL, Johnson CL, Schwartz A (1987) The relationship between the binding site of [3H]-d-cis-diltiazem and that of other non-dihydropyridine calcium entry blockers in cardiac sarcolemma. Mol Pharmacol 31:175–179Google Scholar
  2. Cauvin C, Loutzenhiser R, Van Breemen C (1983) Mechanisms of calcium antagonist-induced vasodilatation. Ann Rev Pharmacol Toxicol 23:373–396Google Scholar
  3. Chatelain P, Demol D, Roba J (1984) Inhibition by suloctidil of [3H]-nitrendipine binding to cerebral cortex membranes. Biochem Pharmacol 33:1099–1103Google Scholar
  4. Ferry DR, Goll A, Gadow C, Glossmann H (1984) (−)-3H-des-methoxyverapamil labelling of putative calcium channels in brain: autoradiographic distribution and allosteric coupling to 1,4-dihydropyridine and diltiazem binding sites. Naunyn-Schmiedeberg's Arch Pharmacol 327:183–187Google Scholar
  5. Gajtkowski GA, Norris DB, Rising TJ, Wood TP (1983) Specific binding of [3H]-tiotidine to histamine H2 receptors in guineapig cerebral cortex. Nature 304:65–67Google Scholar
  6. Glossmann H, Ferry DR, Goll A, Striessnig J, Zernig G (1985) Calcium channels and calcium channel drugs: Recent biochemical and biophysical findings. Arzneim Forsch/Drug Res 35II:1917–1935Google Scholar
  7. Godfraind T, Miller M, Wibo M (1986) Calcium antagonism and calcium entry blockade. Pharmacol Rev 38:321–416Google Scholar
  8. Godfraind T, Polster P (1968) Etude comparative de médicaments inhibant la réponse contractile de vaisseaux isolés d'origine humaine on animale. Therapie 23:1209–1220Google Scholar
  9. Gould RJ, Murphy KMM, Reynolds IJ, Snyder SH (1983) Antischizophrenic drugs of the diphenylbutylpiperidine type act as calcium channel antagonists. Proc Natl Acad Sci USA 80:5122–5125Google Scholar
  10. Gubin J, Chatelain P, Descamps M, Nisato D (1987) European patent No 0235111Google Scholar
  11. McIntosh JAR (1984) Overview of mathematical modeling with computer in endocrinology. In: Rodbard D, Forti G (eds) Computers in endocrinology. Raven Press, New York, pp 37–62Google Scholar
  12. Murphy KMM, Snyder DH (1982) Heterogeneity of adenosine A1 receptor binding in brain tissue. Mol Pharmacol 22:250–257Google Scholar
  13. Murphy KMM, Gould RJ, Largent BL, Snyder SH (1983) An unitary mechanism of calcium antagonist drug action. Proc Natl Acad Sci USA 80:860–864Google Scholar
  14. Nokin P, Clinet M, Schoenfeld P (1983) Cardiac β-adrenoceptor modulation by amiodarone. Biochem Pharmacol 32:2473–2477Google Scholar
  15. Nokin P, Clinet, M, Swillens S, Delisee C, Meysmans L, Chatelain P (1986) Allosteric modulation of [3H]-nitrendipine binding to cardiac and cerebral cortex membranes by amiodarone. J Cardiovasc Pharmacol 8:1051–1057Google Scholar
  16. Pedigo NW, Reisine TD, Fields JZ, Yamamura HI (1978) 3H-Spiroperidol binding to two receptor sites in both the corpus striatum and frontal cortex rat brain. Eur J Pharmacol 50: 451–453Google Scholar
  17. Peroutka SJ, Snyder SH (1979) Multiple serotonin receptor: differential binding of [3H]-5-hydroxytryptamine, [3H]-lysergic acid diethylamine and [3H]-spiroperidol. Mol Pharmacol 16:687–699Google Scholar
  18. Qar J, Galizzi JP, Fosset M, Lazdunski M (1987) Receptors for diphenylbutyl-piperidine neuroleptics in brain, cardiac, and smooth muscle membranes. Relationship with receptors for 1,4-dihydropyridines and phenylalkylamines and with Ca2+ channel blockade. Eur J Pharmacol 141: 261–268Google Scholar
  19. Tran VT, Chang RSL, Snyder SH (1978) Histamine H1 receptors identified in mammalian brain membranes with [3H]-mepyramine. Proc Natl Acad Sci USA 75:6290–6294Google Scholar
  20. Vanhoutte PM, Paoletti R (1987) The WHO classification of calcium antagonists. Trends Pharmacol Sci 8:4–5Google Scholar
  21. Waelbroeck M, Robberecht P, Chatelain P, Christophe J (1982) Rat cardiac muscarinic receptors. Effect of guanine nucleotides on high- and low-affinity binding sites. Mol Pharmacol 21:581–588Google Scholar
  22. Williams RS, Dukes DF, Lefkowitz RJ (1981) Subtype specificity of α-adrenergic receptors in rat heart. J Cardiovasc Pharmacol 3:522–531Google Scholar

Copyright information

© Springer-Verlag 1989

Authors and Affiliations

  • P. Nokin
    • 1
  • M. Clinet
    • 1
  • P. Polster
    • 1
  • P. Beaufort
    • 1
  • L. Meysmans
    • 1
  • J. Gougat
    • 2
  • P. Chatelain
    • 1
  1. 1.SanofiSanofi-Labaz Research CenterBrusselsBelgium
  2. 2.Sanofi-Clip Midy Research CenterMontpellier-CedexFrance

Personalised recommendations