title: Endothelin-1 analogues substituted at both position 18 and 19: highly potent endothelin antagonists with no selectivity for either receptor subtype ETA or ETB.
abstract: Novel endothelin-1 (ET-1) analogues which are highly potent endothelin antagonists at both receptor subtype ETA and ETB are reported. The replacement of Asp18 with the Thr18 and of Ile19 with a hydrophobic amino acid whose side-chain branches on the gamma-carbon such as Leu, cyclohexylalanine, and gamma-methylleucine (gamma-MeLeu) resulted in loss of or significantly decreased the biological activity of ET-1, while high affinity for the ETA (IC50 = 0.42-0.70 nM) and ETB (IC50 = 0.17-0.43 nM) receptor was retained. These compounds were shown to have high antagonist activities in ET-1-induced vasoconstriction of porcine coronary artery (pA2 7.4-7.7) and in Sarafotoxin S6c-induced vasoconstriction of rabbit pulmonary artery ([Thr18, gamma-MeLeu19]ET-1: pA2 8.4). Among these compounds, [Thr18, gamma-MeLeu19]ET-1 has the desirable characteristic of possessing no agonist activity at either receptor subtype.
authors.affiliation: Discovery Research Division, Takeda Chemical Industries, Ltd., Ibaraki, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kikuchi
authors.forename: K
authors.initials: K
authors.lastname: Kubo
authors.forename: T
authors.initials: T
authors.lastname: Ohtaki
authors.forename: N
authors.initials: N
authors.lastname: Suzuki
authors.forename: T
authors.initials: T
authors.lastname: Asami
authors.forename: N
authors.initials: N
authors.lastname: Shimamoto
authors.forename: M
authors.initials: M
authors.lastname: Wakimasu
authors.forename: M
authors.initials: M
authors.lastname: Fujino
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D002417:Cattle; D004347:Drug Interactions; D016232:Endothelins / Q000037:antagonists & inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D011817:Rabbits; D017466:Receptors, Endothelin / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013552:Swine
chemical_list: D016232:Endothelins; D017466:Receptors, Endothelin