title: Pharmacologic properties of YM218, a novel, potent, nonpeptide vasopressin V1A receptor-selective antagonist.
abstract: The pharmacologic profile of YM218, (Z)-4'-{4,4-difluoro-5-[2-oxo-2-(4-piperidinopiperidino)ethylidene]-2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carbonyl}-2-methyl-3-furanilide hemifumarate, a newly synthesized, nonpeptide vasopressin (AVP) receptor antagonist, was investigated using several in vitro and in vivo methods. YM218 exhibited high affinity for V1A receptors isolated from rat liver, with a Ki value of 0.50 nM. In contrast, YM218 exhibited much lower affinity for rat pituitary V1B, kidney V2, and uterus oxytocin receptors, with Ki values of 1510 nM, 72.2 nM, and 150 nM, respectively. In vivo studies revealed that YM218 dose-dependently inhibited pressor response to exogenous AVP in pithed rats (intravenous) and in conscious normotensive rats (intravenous or oral) with a long duration of action (>8 h at 3 mg/kg, p.o.). In contrast, oral administration of YM218 did not increase urine excretion in conscious rats. These results demonstrate that YM218 is a potent nonpeptide AVP V1A receptor-selective antagonist that will be useful in future studies to help clarify the physiologic and pathophysiologic roles of AVP.
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: Toshiyuki
authors.initials: T
authors.lastname: Kusayama
authors.forename: Koh-ichi
authors.initials: K
authors.lastname: Wada
authors.forename: Noe
authors.initials: N
authors.lastname: Ishii
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Taniguchi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Takeyuki
authors.initials: T
authors.lastname: Yatsu
authors.forename: Wataru
authors.initials: W
authors.lastname: Uchida
authors.forename: Masayuki
authors.initials: M
authors.lastname: Shibasaki
mesh_terms: D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D005260:Female; D007211:Indoles; D007668:Kidney / Q000187:drug effects*; D008099:Liver / Q000187:drug effects*; D008297:Male; D010880:Piperidines / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D010902:Pituitary Gland / Q000187:drug effects*; D011311:Pressoreceptors / Q000187:drug effects*; D011759:Pyrrolidines; D051381:Rats; D017208:Rats, Wistar; D018045:Receptors, Oxytocin / Q000378:metabolism
chemical_list: C501286:4'-(4,4-difluoro-5-(2-oxo-2-(4-piperidinopiperidino)ethylidene)-2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carbonyl)-2-methyl-3-furanilide; D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D007211:Indoles; D010880:Piperidines; D011759:Pyrrolidines; D018045:Receptors, Oxytocin; C082134:relcovaptan