title: Effects of YM471, a nonpeptide AVP V(1A) and V(2) receptor antagonist, on human AVP receptor subtypes expressed in CHO cells and oxytocin receptors in human uterine smooth muscle cells.
abstract: 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, is a newly synthesized potent vasopressin (AVP) receptor antagonist. Its effects on binding to and signal transduction by cloned human AVP receptors (V(1A), V(1B) and V(2)) stably expressed in Chinese hamster ovary (CHO) cells, and oxytocin receptors in human uterine smooth muscle cells (USMC) were studied. YM471 potently inhibited specific [(3)H]-AVP binding to V(1A) and V(2) receptors with K(i) values of 0.62 nM and 1.19 nM, respectively. In contrast, YM471 exhibited much lower affinity for V(1B) and oxytocin receptors with K(i) values of 16.4 microM and 31.6 nM, respectively. In CHO cells expressing V(1A) receptors, YM471 potently inhibited AVP-induced intracellular Ca(2+) concentration ([Ca(2+)](i)) increase, exhibiting an IC(50) value of 0.56 nM. However, in human USMC expressing oxytocin receptors, YM471 exhibited much lower potency in inhibiting oxytocin-induced [Ca(2+)](i) increase (IC(50)=193 nM), and did not affect AVP-induced [Ca(2+)](i) increase in CHO cells expressing V(1B) receptors. Furthermore, in CHO cells expressing V(2) receptors, YM471 potently inhibited the production of cyclic AMP stimulated by AVP with an IC(50) value of 1.88 nM. In all assays, YM471 showed no agonistic activity. These results demonstrate that YM471 is a potent, nonpeptide human V(1A) and V(2) receptor antagonist which will be a valuable tool in defining the physiologic and pharmacologic actions of AVP.
authors: Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors: J
authors: J
authors: Tsukada
authors: A
authors: A
authors: Tahara
authors: Y
authors: Y
authors: Tomura
authors: Wada Ki
authors: T
authors: T
authors: Kusayama
authors: N
authors: N
authors: Ishii
authors: T
authors: T
authors: Yatsu
authors: W
authors: W
authors: Uchida
authors: N
authors: N
authors: Taniguchi
authors: A
authors: A
authors: Tanaka
mesh_terms: D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001127:Arginine Vasopressin / Q000378:metabolism; D001381:Azepines / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010121:Oxytocin / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology; D011869:Radioligand Assay; D018045:Receptors, Oxytocin / Q000187:drug effects* / Q000378:metabolism; D017483:Receptors, Vasopressin / Q000235:genetics / Q000378:metabolism; D013141:Spiro Compounds / Q000494:pharmacology; D014316:Tritium; D014599:Uterus / Q000187:drug effects* / Q000378:metabolism
chemical_list: 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; D007211:Indoles; D009025:Morpholines; D010880:Piperidines; D011759:Pyrrolidines; D018045:Receptors, Oxytocin; D017483:Receptors, Vasopressin; D013141:Spiro Compounds; D014316:Tritium; D001127:Arginine Vasopressin; D010121:Oxytocin; C103281:satavaptan; C082134:relcovaptan; D000242:Cyclic AMP; D002118:Calcium