title: Effect of a novel bifunctional endothelin receptor antagonist, IRL 3630A, on guinea pig respiratory mechanics.
abstract: This study characterized the in vitro pharmacological properties of a newly developed endothelin receptor antagonist, N-butanesulfonyl-[N-(3, 5-dimethylbenzoyl)-N-methyl-3-[4-(5-isoxazolyl)-phenyl]-(D)- alanyl]-( L)-valineamide sodium salt (IRL 3630A), and its in vivo effects on respiratory mechanics were determined. IRL 3630A showed highly balanced affinities to human endothelin ET(A) and ET(B) receptors, giving apparent K(i) values of 1.5 and 1.2 nM, respectively. This compound also potently antagonized the endothelin-1-induced intracellular Ca(2+) increases in both embryonic bovine tracheal (EBTr) cells expressing endothelin ET(A) receptors and human Girardi heart (hGH) cells expressing endothelin ET(B) receptors. In guinea pig isolated tracheas having both endothelin ET(A) and ET(B) receptors, IRL 3630A greatly inhibited endothelin-1-induced contraction (pA(2)=7.1), which was partially or scarcely suppressed by the endothelin ET(A) receptor antagonist cyclo[-(D)-Trp-(D)-Asp-(L)-Pro-(D)-Val-(L)-Leu-] (BQ-123) or the endothelin ET(B) receptor antagonist N-(3, 5-dimethylbenzoyl)-N-methyl-3-(4-phenyl)-(D)-phenylalanyl-(L)-t ryptop han (IRL 2500), respectively. Bolus i.v. injections of IRL 3630A administered into anaesthetized guinea pigs at 10 and 30 microg/kg inhibited endothelin-1 (1.3 microg/kg)-induced changes in respiratory resistance and compliance in a dose dependent manner, whereas both sodium 2-benzo[1, 3]dioxol-5-yl-4-(4-methoxy-phenyl)-4-oxo-3-(3,4, 5-trimethoxy-benzyl)-but-2-enoate (an endothelin ET(A) receptor antagonist: PD 156707) and IRL 2500 at doses of up to 30 microg/kg did not affect endothelin-1-induced changes in respiratory mechanics, reflecting the in vitro results. IRL 3630A is thus an effective bifunctional endothelin receptor antagonist, and will be useful in clarifying the role of endothelin in pulmonary diseases such as bronchial asthma.
authors.affiliation: Takarazuka Research Institute, Novartis Pharma K.K., 10-66 Miyuki-cho, 665-8666, Takarazuka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Makatani
authors.forename: Y
authors.initials: Y
authors.lastname: Fujitani
authors.forename: M
authors.initials: M
authors.lastname: Takimoto
authors.forename: K
authors.initials: K
authors.lastname: Oda
authors.forename: Y
authors.initials: Y
authors.lastname: Sasaki
authors.forename: S
authors.initials: S
authors.lastname: Hori
authors.forename: T
authors.initials: T
authors.lastname: Inui
authors.forename: J
authors.initials: J
authors.lastname: Sakaki
authors.forename: T
authors.initials: T
authors.lastname: Okada
authors.forename: K
authors.initials: K
authors.lastname: Hoshiko
authors.forename: T
authors.initials: T
authors.lastname: Yamamura
mesh_terms: D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D001667:Binding, Competitive; D001713:Biphenyl Compounds / Q000494:pharmacology; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D006224:Cricetinae; D004149:Dioxoles / Q000494:pharmacology; D004151:Dipeptides / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008170:Lung Compliance / Q000187:drug effects; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000378:metabolism; D015656:Respiratory Mechanics / Q000187:drug effects* / Q000502:physiology; D014132:Trachea / Q000187:drug effects / Q000502:physiology
chemical_list: D001713:Biphenyl Compounds; D004149:Dioxoles; D004151:Dipeptides; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; C098287:IRL 2500; C093321:PD 156707; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D002118:Calcium; C116703:IRL 3461