title: Calmodulin antagonistic action of new 1,5-benzothiazepines derived from diltiazem.
abstract: A series of newly synthesized 1,5-benzothiazepines derived from diltiazem (CAS 42399-41-7) were tested for calmodulin antagonistic activities using Ca(2+)-calmodulin stimulated phosphodiesterase (PDE). Some compounds possessing the benzoyloxy moieties at position 4 of 1,5-benzothiazepine ring of diltiazem showed a dose-dependent inhibitory action with the potencies comparable to that of a calmodulin antagonist, N-(6-aminohexyl)-5-chloro-1-naphthalene-sulfonamide (W-7). In contrast, diltiazem did not exert the inhibitory action at the same concentrations. Further, radioligand binding experiment, using a radiolabeled 1,5-benzothiazepine, showed that these compounds bound to Ca(2+)-calmodulin complex, but not to calmodulin in the presence of EGTA, suggesting that these 1,5-benzothiazepines are new calmodulin antagonists. Some of these compounds inhibited [3H]diltiazem binding to Ca antagonist binding sites in cell membranes of rat cerebral cortex but with a less potent affinities than diltiazem, suggesting that there was no correlation between their anti-calmodulin effect and the binding affinity to Ca antagonist binding sites. In conclusion, new 1,5-benzothiazepines have been demonstrated to have an anti-calmodulin action. These compounds may possess a pharmacological activity based on their anti-calmodulin action in addition to their interaction with Ca channel.
authors.affiliation: Biological Research Laboratory, Tanabe Seiyaku Co., Ltd., Saitama, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Suzuki
authors.forename: M
authors.initials: M
authors.lastname: Ohashi
authors.forename: O
authors.initials: O
authors.lastname: Takaiti
authors.forename: S
authors.initials: S
authors.lastname: Harigaya
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D002147:Calmodulin / Q000037:antagonists & inhibitors*; D002417:Cattle; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D002746:Chlorpromazine / Q000494:pharmacology; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D004110:Diltiazem / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology; D013841:Thiazepines / Q000494:pharmacology*
chemical_list: D015220:Calcium Channels; D002147:Calmodulin; D013449:Sulfonamides; D013841:Thiazepines; C017967:W 7; D010727:Phosphoric Diester Hydrolases; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D004110:Diltiazem; D002746:Chlorpromazine