Drug binding in cardiac calcium channels : Identification and its application to drug development

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In this project, we aim to reveal binding sites for calcium antagonists in cardiac calcium channels by photoaffinity laveling and the results are to be applied to design and synthesis of new drugs. New findings are as follows. (1) Benzothiazepine binding sites were identified in segment 5 and 6 in repeat IV by photoaffinity labeling using azidobutyryl clentiazem with a rather small-sized photoprobe. The recent report by foreign investigaters where two labeled sites in repeat III and IV must be a wrong conclusion resulted from using a bulky photoprobe with long side chain. (2) We revealed the binding site of semotiadil, a new typed calcium antagonist of 1,4-benzothiazine structure 1^^- which is homologous to benzothiazepine 2^^- but the identified sites were different. Theidentified site by photoaffinity labeling was solely in S6 of repeat IV which was partly shared with other calcium antagonist binding sites but not overlapped completely. The results can explain the pharmacological interactions among these drugs. (3) We also identified the semotiadil sites in cardiac channel, which were identical to the skeletal muscle counterpart but some amino acids were substituted. The substitution can be interpreted to dominate the difference of binding affinity and tissue selectivity in part in two calcium channels. (4) Three dimentional structures of 1 and 2 are not ovelapped by x-ray crystallographic analysis. It suggests that we will design and synthesis of improved calcium antagonists which are derived from 2 as a lead compound.