Development of the 4th generation calcium antagonists based on molecular revealing the binding sites in calcium channels

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In this project, we aim to reveal binding sites for calcium antagonists in cardiac calcium channels by photoaffinity labeling and the results are to be applied to design and synthesis of new drugs. New findings are as follows. (1) We identified the dihydropyridine 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 in two calcium channels. (2) 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. (3) We revealed the binding site of a new typed calcium antagonist of 1, 4-benzothiazine structure I which is homologous to benzothiazepine 2 but the identified sites were different. The results can explain the pharmacological difference between two drugs. (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.