title: Synthesis and pharmacological profile of non-peptide vasopressin antagonists.
abstract: 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.
authors.affiliation: Department of Medicinal/Pharmaceutical Chemistry, University of Vienna, A-1090 Vienna, Althanstrasse 14, Austria.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Galanski
authors.forename: Thomas
authors.initials: T
authors.lastname: Erker
authors.forename: Christian R
authors.initials: CR
authors.lastname: Studenik
authors.forename: Majidreza
authors.initials: M
authors.lastname: Kamyar
authors.forename: Pakiza
authors.initials: P
authors.lastname: Rawnduzi
authors.forename: Martina
authors.initials: M
authors.lastname: Pabstova
authors.forename: Rosa
authors.initials: R
authors.lastname: Lemmens-Gruber
mesh_terms: D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D006168:Guinea Pigs; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology; D013329:Structure-Activity Relationship; D014667:Vasopressins / Q000037:antagonists & inhibitors*
chemical_list: D065092:Antidiuretic Hormone Receptor Antagonists; D014667:Vasopressins