title: [Pharmacology of conivaptan hydrochloride (YM087), a novel vasopressin V1A/V2 receptor antagonist].
abstract: Pharmacology of conivaptan hydrochloride (YM087) was investigated in in vitro and in vivo studies. In radioligand binding study, YM087 showed high affinity for both V1A and V2 receptors in animal and human species. Affinity of YM087 for V1A and V2 receptors was comparable to that of vasopressin (AVP). In functional antagonistic activity study, YM087 concentration-dependently inhibited AVP-induced intracellular Ca2+ elevation via human V1A receptors and AVP-stimulated cAMP accumulation via human V2 receptors. Intravenous administration of YM087 dose-dependently inhibited AVP-induced pressor responses and produced a dose-dependent aquaresis in rats and dogs. Oral administration of YM087 showed a potent and long-lasting antagonistic activity on V1A and V2 receptors. YM087 was effective in dogs with heart failure and in heart failure rats with hyponatremia and edema. These results reveal that YM087 is the first orally active V1A/V2 receptor antagonist and suggest that YM087 may be useful in the treatment of congestive heart failure and hyponatremia.
authors.affiliation: Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Yatsu
authors.forename: Y
authors.initials: Y
authors.lastname: Tomura
authors.forename: A
authors.initials: A
authors.lastname: Tahara
authors.forename: K
authors.initials: K
authors.lastname: Wada
authors.forename: T
authors.initials: T
authors.lastname: Kusayama
authors.forename: J
authors.initials: J
authors.lastname: Tsukada
authors.forename: A
authors.initials: A
authors.lastname: Tanaka
authors.forename: Y
authors.initials: Y
authors.lastname: Iizumi
authors.forename: K
authors.initials: K
authors.lastname: Honda
mesh_terms: D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines / Q000008:administration & dosage / Q000494:pharmacology*; D002118:Calcium / Q000032:analysis; D000242:Cyclic AMP / Q000032:analysis; D004285:Dogs; D005260:Female; D006333:Heart Failure / Q000188:drug therapy; D006801:Humans; D007010:Hyponatremia / Q000188:drug therapy; D066298:In Vitro Techniques; D008297:Male; D011869:Radioligand Assay; D051381:Rats; D014667:Vasopressins / Q000494:pharmacology
chemical_list: D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; C106389:conivaptan; D014667:Vasopressins; D000242:Cyclic AMP; D002118:Calcium