title: Antagonist activity of [Thr18,gamma-methylleucine19]endothelin-1 in human endothelin receptors.
abstract: Receptor binding and antagonist properties of endothelin-1 analogues, [Thr18,gamma-methylleucine19]endothelin-1, [Thr18,Leu19]endothelin-1 and [Thr18,cyclohexylalanine19]endothelin-1, were investigated using cloned human endothelin ET(A) and ET(B) receptors expressed in Chinese hamster ovary cells. Among them, [Thr18,gamma-methylleucine19]endothelin-1 had a high affinity for endothelin ET(A) and ET(B) receptors with respective Kd values of 300 and 110 pM and had no agonist activity on the stimulation of arachidonic acid release in endothelin ET(A) and ET(B) receptor-expressing cells. [Thr18,gamma-methylleucine19]Endothelin-1 had potent antagonist activity in endothelin-1-induced arachidonic acid release in endothelin ET(A) and ET(B) receptor-expressing cells with respective pA2 values of 8.2 and 8.5. In an inositol phosphates accumulation assay, [Thr18,gamma-methylleucine19]endothelin-1 also exhibited potent antagonist activity for endothelin ET(A) and ET(B) receptors with respective pA2 values of 8.0 and 8.4. In conclusion, [Thr18,gamma-methylleucine19]endothelin-1 acts as a potent and nonselective antagonist with no agonist activity for cloned human endothelin ET(A) and ET(B) receptors.
authors.affiliation: Discovery Research Laboratories I, Takeda Chemical Industries, Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Masuda
authors.forename: T
authors.initials: T
authors.lastname: Sugo
authors.forename: T
authors.initials: T
authors.lastname: Kikuchi
authors.forename: M
authors.initials: M
authors.lastname: Satoh
authors.forename: Y
authors.initials: Y
authors.lastname: Fujisawa
authors.forename: Y
authors.initials: Y
authors.lastname: Itoh
authors.forename: M
authors.initials: M
authors.lastname: Wakimasu
authors.forename: T
authors.initials: T
authors.lastname: Ohtaki
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001667:Binding, Competitive; D016466:CHO Cells; D003001:Cloning, Molecular; D006224:Cricetinae; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D016232:Endothelins / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D006868:Hydrolysis; D007700:Kinetics; D010716:Phosphatidylinositols / Q000378:metabolism; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; D010716:Phosphatidylinositols; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D011994:Recombinant Proteins; C106975:endothelin-1, Thr(18)-Cha(19)-; C106977:endothelin-1, Thr(18)-Leu(19)-; C086099:endothelin-1, Thr(18)-gamma-methyl-Leu(19)-; D016718:Arachidonic Acid