Effects of YM218, a nonpeptide vasopressin V1A receptor-selective antagonist, on human vasopressin and oxytocin receptors.
The binding and signal transduction characteristics 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, potent arginine vasopressin (AVP) V(1A) receptor-selective antagonist, were examined using cloned human AVP receptors (V(1A), V(1B) and V(2)) stably expressed in Chinese hamster ovary (CHO) cells and human uterine smooth muscle cells (USMCs) expressing oxytocin receptors. YM218 potently inhibited specific binding of [(3)H] AVP to V(1A) receptors, exhibiting a K(i) value of 0.30 nM. In contrast, YM218 exhibited much lower affinity for V(1B), V(2) and oxytocin receptors, exhibiting K(i) values of 25,500 nM, 381 nM and 71.0 nM, respectively. In CHO cells expressing V(1A) receptors, YM218 potently inhibited the AVP-induced increase in intracellular Ca(2+) concentration ([Ca(2+)](i)), exhibiting an IC(50) value of 0.25 nM. However, in human USMCs expressing oxytocin receptors, YM218 exhibited a much lower potency in inhibiting the oxytocin-induced [Ca(2+)](i) increase, showing an IC(50) value of 607 nM, and had no effect on the AVP-induced [Ca(2+)](i) increase in CHO cells expressing V(1B) receptors. Furthermore, in CHO cells expressing V(2) receptors, YM218 did not potently inhibit the production of cAMP stimulated by AVP, showing an IC(50) value of 62.2 nM. In all assays used, YM218 did not exhibit any agonistic activity. These results demonstrate that YM218 is a potent, nonpeptide human V(1A) receptor-selective antagonist, and that YM218 will be a valuable new tool to gain further insight into the physiologic and pharmacologic actions of AVP.
Tahara
Atsuo
A
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. tahara@yamanouchi.co.jp
Tsukada
Junko
J
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; D001127:Arginine Vasopressin / Q000378:metabolism; D001552:Benzazepines / Q000378:metabolism / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D010880:Piperidines / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D018045:Receptors, Oxytocin / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D017483:Receptors, Vasopressin / Q000378:metabolism / Q000502:physiology; D015290:Second Messenger Systems / Q000187:drug effects; D014667:Vasopressins / 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; D010880:Piperidines; D018045:Receptors, Oxytocin; D017483:Receptors, Vasopressin; C106389:conivaptan; D014667:Vasopressins; D001127:Arginine Vasopressin