title: Effects of YM218, a nonpeptide vasopressin V1A receptor-selective antagonist, on human vasopressin and oxytocin receptors.
abstract: 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.
authors.affiliation: Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. tahara@yamanouchi.co.jp
authors.forename: Atsuo
authors.initials: A
authors.lastname: Tahara
authors.forename: Junko
authors.initials: J
authors.lastname: Tsukada
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; 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
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; D010880:Piperidines; D018045:Receptors, Oxytocin; D017483:Receptors, Vasopressin; C106389:conivaptan; D014667:Vasopressins; D001127:Arginine Vasopressin