( sup 3 H)TA-3090, a selective benzothiazepine-type calcium channel receptor antagonist: In vitro characterization

Journal Article · Tue May 01 00:00:00 EDT 1990 · Journal of Pharmacology and Experimental Therapeutics; (USA)

OSTI ID:6727859

Zobrist, R H; Mecca, T E ^[1]

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1. Marion Merrell Dow Inc., Kansas City, MO (USA)

Binding of the new benzothiazepine calcium channel blocker, (+)-(2S,3S)-3-acetoxy-8-chloro-5-(2-(dimethylamino)ethyl)-2,3-dihydro-2- (4- methoxyphenyl)-1,5-benzothiazepine-4-(5H)-one maleate, (3H)TA-3090, was characterized and its specificity for rat myocardial benzothiazepine receptors described. Scatchard plots and nonlinear regression analysis of specific (3H)TA-3090 binding best fit a one-site binding model (Kd = 8.8 +/- 2.7 nM, Bmax = 132 +/- 38 fmol/mg protein). Kinetically derived affinity constants were in close agreement (Kd = 7.86 nM) with those obtained from analysis of equilibrium binding data. In comparison, under identical conditions (3H)diltiazem exhibited a Kd of 38 nM and Bmax, 106 fmol/mg protein. Specific binding was saturable, reversible and stereoselective (d-cis-TA-3090 Ki = 14 nM; 1-cis-TA-3090 Ki = 2700 nM). Competitions for (3H)TA-3090 binding were conducted with nifedipine, propranolol, prazosin, quinuclidinyl benzilate, verapamil and yohimbine. Only the calcium channel blockers nifedipine and verapamil inhibited specific (3H)TA-3090 binding. Nifedipine could maximally inhibit only 52% of specifically bound (3H)TA-3090 at 10 microM. In contrast, however, 10 microM verapamil completely inhibited specific radioligand binding (Ki = 93 +/- 28 nM) but with six times less efficacy than TA-3090. Thus, these data demonstrate that (3H)TA-3090 is a potent radioligand selective for the benzothiazepine binding site and is consistent with the hypothesis that (3H)TA-3090 interacts with a myocardial benzothiazepine receptor site.

• OSTI ID: 6727859
• Journal Information: Journal of Pharmacology and Experimental Therapeutics; (USA), Vol. 253:2; ISSN 0022-3565
• Country of Publication: United States
• Language: English

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