Benzothiazepines binding site

Dihydrotetrazolo[5,l-cf][l,5]benzothiazepines (102) were synthesized by nitrous acid treatment of 2,3-dihydro-1,5-benzothiazepin-4-ylhydrazines (101), which were prepared from 2,3-dihydro-l,5-benzothia-zepine-4(5//)-thiones (84) by reaction with hydrazine hydrate in tetrahydrofuran (THF) (Scheme 31) (88JHC1399 89MI2 93F665). The ability of compounds 103 to displace specific [3H]flunitrazepam binding was studied. Only compounds with a chlorine atom at the 9-position were able to interact with [3H]flunitrazepam binding sites (93F665). 

Annexins isolated from chondroblast matrix vesicles may be reconstituted with phospholipids to form calcium ion channels in the complete absence of Ca2+ ions. Indeed, annexin V has domains that directly bind calcium ions glutamate and aspartate residues provide the ion binding site (EF-hand domains). Figure 9.6b illustrates putative annexin V channels that mediate an influx of Ca2+ ions into artificial bilayers and liposomes (detectable with a calcium-sensitive fluorescent dye). These in vitro annexin Ca2+ channels, and also the Ca2+ influx into matrix vesicles in cell culture and in vivo, are blocked by Zn2+ ions, or a derivative of 1,4-benzothiazepine (inhibitor K201). 

Tetrandrine, a traditional medicinal alkaloid, has been used in China for the treatment of hypertension, cardiac arrhythmia, and angina pectoris. Recently, it has been shown that tetrandrine blocks voltage activated L-type Ca++ channels in a variety of excitable cells including cardiac tissue. The binding site of tetrandrine is located at the benzothiazepine receptor on the aj-subunit of the channel. It is clear that tetrandrine s actions in the treatment of cardiovascular diseases, including hypertension and supraventricular arrhythmia, are due primarily to its blocking of voltage activated L-type and T-type 08" + channels. 

The dihydropyridine- (DHP)-sensitive calcium channel purified from skeletal muscle is composed of five subunits al9 a2, P, y, and 8 (9-12). The cty subunit (molecular weight Mr 170 kD) forms a functional voltage-gated calcium channel (9, 13-15) and contains the binding sites for the three classes of calcium channel modulators 1,4-dihydropyridines (16), phenylal-kylamines, and benzothiazepines (17). The primary structure of the ax subunit was first elucidated from skeletal muscle (18) highly homologous sequences have since been cloned from cardiac muscle (13, 19, 20) and brain (21), aorta (22), and lung (23) tissue. 

Bisbenzylisoquinoline alkaloids block Ca+2 uptake through L-type Ca+2 channel and modulate binding of ligands to four distinct sites (dihydropyridine, benzothiazepine, aralkylamine, and (diphenylbutyl)piperidine) in the Ca+2 entry blocker receptor complex of the channel. All bisbenzylisoquinoline analogs tested, including oxyacanthine, completely inhibit diltiazem binding,... 

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