Pharmacologic properties of YM218, a novel, potent, nonpeptide vasopressin V1A receptor-selective antagonist.
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.
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
Kusayama
Toshiyuki
T
Wada
Koh-ichi
K
Ishii
Noe
N
Taniguchi
Nobuaki
N
Suzuki
Takeshi
T
Yatsu
Takeyuki
T
Uchida
Wataru
W
Shibasaki
Masayuki
M
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
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