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 K i 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 K i 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.
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References
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 31:175–179
Cauvin C, Loutzenhiser R, Van Breemen C (1983) Mechanisms of calcium antagonist-induced vasodilatation. Ann Rev Pharmacol Toxicol 23:373–396
Chatelain P, Demol D, Roba J (1984) Inhibition by suloctidil of [3H]-nitrendipine binding to cerebral cortex membranes. Biochem Pharmacol 33:1099–1103
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 327:183–187
Gajtkowski GA, Norris DB, Rising TJ, Wood TP (1983) Specific binding of [3H]-tiotidine to histamine H2 receptors in guineapig cerebral cortex. Nature 304:65–67
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:1917–1935
Godfraind T, Miller M, Wibo M (1986) Calcium antagonism and calcium entry blockade. Pharmacol Rev 38:321–416
Godfraind T, Polster P (1968) Etude comparative de médicaments inhibant la réponse contractile de vaisseaux isolés d'origine humaine on animale. Therapie 23:1209–1220
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 80:5122–5125
Gubin J, Chatelain P, Descamps M, Nisato D (1987) European patent No 0235111
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 37–62
Murphy KMM, Snyder DH (1982) Heterogeneity of adenosine A1 receptor binding in brain tissue. Mol Pharmacol 22:250–257
Murphy KMM, Gould RJ, Largent BL, Snyder SH (1983) An unitary mechanism of calcium antagonist drug action. Proc Natl Acad Sci USA 80:860–864
Nokin P, Clinet M, Schoenfeld P (1983) Cardiac β-adrenoceptor modulation by amiodarone. Biochem Pharmacol 32:2473–2477
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 8:1051–1057
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: 451–453
Peroutka SJ, Snyder SH (1979) Multiple serotonin receptor: differential binding of [3H]-5-hydroxytryptamine, [3H]-lysergic acid diethylamine and [3H]-spiroperidol. Mol Pharmacol 16:687–699
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: 261–268
Tran VT, Chang RSL, Snyder SH (1978) Histamine H1 receptors identified in mammalian brain membranes with [3H]-mepyramine. Proc Natl Acad Sci USA 75:6290–6294
Vanhoutte PM, Paoletti R (1987) The WHO classification of calcium antagonists. Trends Pharmacol Sci 8:4–5
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 21:581–588
Williams RS, Dukes DF, Lefkowitz RJ (1981) Subtype specificity of α-adrenergic receptors in rat heart. J Cardiovasc Pharmacol 3:522–531
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Nokin, P., Clinet, M., Polster, P. et al. SR 33557, a novel calcium-antagonist: interaction with [3H]-(±)-nitrendipine and [3H]-(−)-desmethoxy-verapamil binding sites in cerebral membranes. Naunyn-Schmiedeberg's Arch Pharmacol 339, 31–36 (1989). https://doi.org/10.1007/BF00165122
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DOI: https://doi.org/10.1007/BF00165122