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Trichloroacetamidines, a new class of positive inotropic agents

1978; American Chemical Society; Volume: 21; Issue: 12 Linguagem: Inglês

10.1021/jm00210a021

1520-4804

Walfred S. Saari, Mark B. Freedman, Joel R. Huff, Stella W. King, A. W. RAAB, Susan J. Bergstrand, Edward L. Engelhardt, Alexander Scriabine, G. W. Morgan,

Synthesis and Reactions of Organic Compounds

A series of trichloroacetamidine derivatives, obtained by addition of amines to trichloroacetonitrile, was evaluated for positive inotropic activity on isolated cat heart papillary muscles. Increased contractility, not antagonized by beta-adrenergic blockade with sotalol or reserpine pretreatment, was observed in this assay with a variety of N-substituted trichloroacetamidine derivatives. More extensive pharmacological studies with the 3-indolylmethyl analogue 2 showed that this amidine in dogs, 5 mg/kg iv, produced a positive inotropic effect more pronounced than that of ouabain, 50 microgram/kg iv. Several of the trichloroacetamidines were found to be inhibitors of guinea pig kidney and calf heart Na-K-dependent ATPase and to have specificity for these enzymes different from that of ouabain. Bacterial mutagenic activity was observed with three members, 2,3, and 12, of the series.