Studies on the chemistry of thienoanellated O, N- and S, N-containing heterocycles. Part 30: Synthesis and pharmacological properties of thieno[2,3- b][1,4]thiazines with potential vasopressin receptor antagonistic activity

• Published in: Bioorganic & medicinal chemistry Vol. 14; no. 3; pp. 826 - 836
• Main Authors: Galanski, Maria E., Erker, Thomas, Handler, Norbert, Lemmens-Gruber, Rosa, Kamyar, Majidreza, Studenik, Christian R.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.02.2006; Elsevier Science
• Subjects: Animals; Antidiuretic Hormone Receptor Antagonists; Aorta - drug effects; Aorta - physiology; Arginine Vasopressin - pharmacology; Biological and medical sciences; Bridged Bicyclo Compounds, Heterocyclic - chemical synthesis; Bridged Bicyclo Compounds, Heterocyclic - chemistry; Bridged Bicyclo Compounds, Heterocyclic - metabolism; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Female; Guinea Pigs; Heart Atria - drug effects; Ileum - drug effects; Ileum - physiology; In Vitro Techniques; Male; Medical sciences; Muscle Relaxation - drug effects; Myocardial Contraction - drug effects; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Papillary muscles; Papillary Muscles - drug effects; Papillary Muscles - physiology; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Pulmonary Artery - drug effects; Pulmonary Artery - physiology; Receptors, Vasopressin - metabolism; Right atria; Terminal ilea; Thiazines - chemical synthesis; Thiazines - chemistry; Thiazines - metabolism; Thiazines - pharmacology; Thieno[2,3- b][1,4]thiazines; Vascular smooth muscles; Vasodilation - drug effects; Vasopressin receptor antagonistic activity; Terminal ilea; Thieno[2,3- b][1,4]thiazines; Papillary muscles; Guinea pigs; Vasopressin receptor antagonistic activity; Vascular smooth muscles; Right atria; Heart; Non peptide compound; Smooth muscle; Guinea pig; Antispasmodic agent; Blood vessel; Antagonist; Chemical synthesis; Thieno[2,3-b][1,4]thiazines; Right atrium; Vasopressin receptor; Vasopressin receptor antagonistic activity: Vascular smooth muscles; Papillary muscle; Rodentia; Benzene derivatives; Muscle contraction; Ileum; In vitro; Biological activity; Vertebrata; Mammalia; Side chain; Animal
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2005.09.001

A series of new nonpeptide vasopressin antagonists with a 6-ethyl-thieno[2,3- b][1,4]thiazine or 6-benzyl-thieno[2,3- b][1,4]thiazine skeleton and structural modifications of the aryl side chain were synthesized in this study. The effects on guinea pig heart and smooth muscle preparations were investigated. In the presence of AVP the compounds showed an antagonistic effect. The compounds did not change spontaneous rate in right atria and exerted a slight but not significant negative inotropic effect in papillary muscles. The relaxing effect on vascular smooth muscle and terminal ileum was far more pronounced. Generally the relaxing effect on terminal ilea was more potent maybe due to difference in V 1a receptor density. Our results demonstrate that compounds with an ethyl group in position six on the thienothiazine ring ( 14, 16, 18 and 22) exerted the most potent relaxing activity in terminal ilea, whereas compounds with a phenyl ring in position six reduced this effect.