Synthesis and pharmacological profile of non-peptide vasopressin antagonists

Recently we presented a series of 6-ethyl and 6-benzylthieno[2,3-b][1,4]thiazine derivatives with relaxing effects on vascular smooth muscle and terminal ileum. In this report the synthesis of further thieno[2,3-b][1,4]thiazine derivatives and related compounds with a thieno[2,3-b][1,4]thiazepine or thieno[3,2-b][1,4]thiazine ring system is described. The pharmacological effect of the agents was tested in isolated smooth (terminal ileum, pulmonary artery, aortic rings, myometrial strips) and heart (papillary muscle, spontaneously beating right atrium) muscle preparations of the guinea pig. Contractions were measured isometrically, and smooth muscle preparations were either precontracted with high K+ (60 or 90 mM KCl containing nutrient solution) or with agonists, while papillary muscles were electrically stimulated (1 Hz). The vasopressin antagonistic activity of the test compounds was tested in isolated papillary muscles in which the V1A-receptor subtype is located. The biphasic response to vasopressin was antagonized, dependent on the chemical structure of the test compound. Thieno[3,2-b][1,4]thiazines were more potent than thieno[2,3-b][1,4]thiazine and thieno[2,3-b][1,4]thiazepine compounds. In addition, substitution of a methyl substituted terminal benzyl ring instead of a phenyl- or dichlorobenzoyl moiety attenuated the vasopressin antagonistic effect.