title: Pharmacological characterization of YM471, a novel potent vasopressin V(1A) and V(2) receptor antagonist.
abstract: The pharmacologic profile of YM471 ((Z)-4'-[4,4-difluoro-5-[2-(4-dimethylaminopiperidino)-2-oxoethylidene]-2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carbonyl]-2-phenylbenzanilide monohydrochloride), a novel potent vasopressin V(1A) and V(2) receptor antagonist, was investigated using several in vitro and in vivo techniques. YM471 showed high affinity for rat vasopressin V(1A) and V(2) receptors, exhibiting K(i) values of 0.16 and 0.77 nM, respectively. In contrast, YM471 exhibited much lower affinity for rat vasopressin V(1B) and oxytocin receptors, with K(i) values of 10.5 microM and 31.0 nM, respectively. In conscious rats, oral administration of YM471 (0.1-3.0 mg/kg) produced dose-dependent inhibition of the pressor response caused by exogenous vasopressin and increased urine excretion and decreased urine osmolality; this effect lasted more than 8 h. In all biological assays used, YM471 exhibited no agonistic activity. These results demonstrate that YM471 exerts potent and long-lasting antagonistic activity on both vasopressin V(1A) and V(2) receptors, and that this compound may be a useful tool for clarifying the physiologic and pathophysiologic roles of vasopressin and the therapeutic usefulness of the vasopressin receptor antagonist.
authors.affiliation: Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co. Ltd., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Tsukada
authors.forename: Atsuo
authors.initials: A
authors.lastname: Tahara
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Tomura
authors.forename: Koh ichi
authors.initials: Ki
authors.lastname: Wada
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kusayama
authors.forename: Noe
authors.initials: N
authors.lastname: Ishii
authors.forename: Motonori
authors.initials: M
authors.lastname: Aoki
authors.forename: Takeyuki
authors.initials: T
authors.lastname: Yatsu
authors.forename: Wataru
authors.initials: W
authors.lastname: Uchida
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Taniguchi
authors.forename: Akihiro
authors.initials: A
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001381:Azepines / Q000494:pharmacology*; D003655:Decerebrate State; D003681:Dehydration / Q000503:physiopathology / Q000652:urine; D004231:Diuresis / Q000187:drug effects; D004232:Diuretics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005665:Furosemide / Q000494:pharmacology; D008297:Male; D009994:Osmolar Concentration; D010880:Piperidines / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D014667:Vasopressins / Q000494:pharmacology
chemical_list: C432083:4'-(4,4-difluoro-5-(2-(4-dimethylaminopiperidino)-2-oxoethylidene)-2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carbonyl)-2-phenylbenzanilide; D065092:Antidiuretic Hormone Receptor Antagonists; D001381:Azepines; D004232:Diuretics; D010880:Piperidines; D014667:Vasopressins; D005665:Furosemide