Pharmacological characterization of YM471, a novel potent vasopressin V(1A) and V(2) receptor antagonist.
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.
Tsukada
Junko
J
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co. Ltd., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
Tahara
Atsuo
A
Tomura
Yuichi
Y
Wada
Koh ichi
Ki
Kusayama
Toshiyuki
T
Ishii
Noe
N
Aoki
Motonori
M
Yatsu
Takeyuki
T
Uchida
Wataru
W
Taniguchi
Nobuaki
N
Tanaka
Akihiro
A
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
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