Benzothiazepines selectivity

Greco, G., Novellino, E., Fiorini, I., Nacci, V., Campiani, G., Ciani, S.M., Garofalo, A., Bernas-coni, R and Mennini, T. (1994). A Comparative Molecular Field Analysis Model for 6-Arylpyr-rolo(2,l-d)(l,5)Benzothiazepines Binding Selectively to the Mitochondrial Benzodiazepine Receptor. J.Med.Chem., 37,4100-4108. 

Based on the cyclic-blocking moieties and other substituent groups, subtype-selective muscarinic antagonists can be classified into eight groups (l)tricyclic benzodiazepines, (2) benzothiazepines, (3) quinuclidines, (4) poly-methylene tetramines, (5)indenes, ( 6)sila-difenidols, (7) diphenylacetyloxy derivatives, and (.8) himbacine akaloids. 

The first such inhibitors consisted of the coupling of two bile acid molecules by means of a spacer to allow simultaneous interaction with more than one transporter site, resulting in an efficient inhibition of bile acid reabsorption without or with only low absorption of the inhibitor itself (110) (Fig. 8.13). Recently, it was shown that a benzothiazepine derivative, 2164U90, was able to selectively inhibit active ileal bile acid absorption in rats, mice, mon-... 

Calcium-entry blockers include those agents that are selective for slow calcium channels in the myocardium (slow channel blockers) and consist of the following categories of substances benzothiazepines (diltiazem and dihydropy-ridines)—nifedipine, nicardipine, niludipine, nimodipine, nisoldipine, nitrendipine, ryosidine, amlodipine, azodipine, dazodipine, felodipine, flordipine, iodipine, isradipine, mesu-dipine, oxodipine, and riodipine and, phenylalkylamines— verapamil, gallopamil, anipamil, desmethoxyverapamil, emopamil, falipamil, and ronipamil. 

Calcium-channel blockers in current clinical usage affect the slow L-type channel. They are usually classified by their chemical structure, which determines their selectivity for vascular smooth muscle over myocardium, and hence their potential to slow the heart rate (negative inotropic activity) see Table 23. T, (below). Interactions due to additive inotropic effects will therefore apply only to the benzothiazepine (diltiazem) and phenyla-Ikylamine-type (verapamil) calcium-channel blockers, and usually not to the dihydropyridine-type (e.g. nifedipine) calcium-channel blockers. All three types of calcium-channel blocker will have additive hypotensive effects with other drugs with blood-pressure lowering activity. 

A series of selective D2 dopamine receptor agonists were discovered and optimized to obtain benzothiazepine amide 161, a lead compound that possessed good in vitro physical properties, metaboHc stabihty, and in vivo pharmacokinetics (14JME3450). A number of 8-alkoxy-4,5-dihydrobenzo[l)] [l,2,4]triazolo[4,3-(/][l,4]thiazepine derivatives were synthesized, with compound 162 showing potent anticonvulsant activity (14JEIM272). 

Seven-membered Rings.—In an earlier Section, the ring expansion of 2,3-dihydrobenzothiapyran-4-ones was discussed. A preliminary report in which benzothiazepinones were obtained has been followed by the full paper in which the further scope of this transformation is discussed. The first example of a [2 + 2]cycloaddition of benzisothiazoles with vinyl ethers has been reported. Ring expansion to 1,4-benzothiazepine analogues (310) occurs in 80% yield. In a similar study benzothiazoles have been shown to react in a regio-and stereo-selective manner to give the 1,5-benzothiazepine derivatives (311). 

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