Structure–activity relationships of new thienothiazine derivatives in isolated heart and smooth muscle preparations of guinea pigs

Abstract

New thienothiazine derivatives that differ in their side chains on the nitrogen atom of the thienothiazine ring were investigated regarding structure–activity relationships and calcium antagonistic and/or potassium channel opening properties. Isometric contraction force was measured in guinea pig papillary muscles, aortic strips, and terminal ilea. Chronotropic activity was studied in right atria of guinea pigs. The derivatives with a dimethylaminoethylcarboxamide side chain (HO 4) and with a dimethoxyphenylethyl-N-methylaminoethylcarboxamide side chain (HO 7) had the most potent negative inotropic effects on papillary muscles and spontaneously beating right atria. The negative inotropic and chronotropic effects of the compounds with a methylpiperazinylcarbonyl side chain (HO 5) or a diethylaminopropylcarboxamide side chain (HO 6) were less pronounced. The negative inotropic action was reversed by increasing the extracellular calcium concentration. It was also reversed by glibenclamide, for concentrations of the compounds up to the EC 50, but not at higher compound concentrations. Among all the compounds studied, HO 7 had the strongest relaxing effect on aortic strips and terminal ilea. The effects of the derivatives on the smooth muscles could not be reversed by glibenclamide. The calcium antagonistic effect of the thienothiazine derivatives is more pronounced than the potassium channel opening activity, at least in high drug concentrations. Compounds with an aromatic or heterocyclic ring in the side chain have the weakest negative inotropic and negative chronotropic effects on papillary muscles and right atria. However, HO 7 showed a tissue specifity with the most potent relaxing effect on aortic strips and terminal ilea.