[Ala1,3,11,15]endothelin-1 analogs with ETB agonistic activity.
A linear peptide analog of endothelin (ET)-1, [Ala1,3,11,15]ET-1 (4AlaET-1), and its truncated peptide analogs were synthesized to study the structural requirements of ET-1 for the recognition of ETs-nonselective ETB receptors. ET-1 exhibited sub-nanomolar binding to two distinct ET receptor subtypes (ETA and ETB), but 4AlaET-1 bound to ETB with an affinity 1,700 times higher than that seen during binding to ETA. The truncated linear peptides 4AlaET-1(6-21), 4AlaET-1(8-21) and N-acetyl-4AlaET-1(10-21) still had high affinity for ETB, whereas 4AlaET-1(6-20) and 4AlaET-1(11-21) displayed remarkably reduced affinity for ETB. Therefore, ET-1 requires the Glu10-Trp21 sequence for ETB binding, but not the disulfide bridges. These ETB-binding peptides elicit endothelium-dependent vasorelaxation of porcine pulmonary arteries in parallel with the binding affinity for ETB, suggesting that they are ETB agonists.
Saeki
T
T
Central Research Labs., Banyu Pharmaceutical Co., Ltd., Tokyo, Japan.
Ihara
M
M
Fukuroda
T
T
Yamagiwa
M
M
Yano
M
M
D000595:Amino Acid Sequence; D000818:Animals; D001011:Aorta / Q000378:metabolism; D001667:Binding, Competitive; D002462:Cell Membrane / Q000378:metabolism; D002531:Cerebellum / Q000378:metabolism; D016232:Endothelins / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D066298:In Vitro Techniques; D007700:Kinetics; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism*; D017466:Receptors, Endothelin; D013329:Structure-Activity Relationship; D013552:Swine; D014664:Vasodilation / Q000187:drug effects
D016232:Endothelins; D010456:Peptides, Cyclic; D011956:Receptors, Cell Surface; D017466:Receptors, Endothelin; C061779:endothelin 1, Ala(1,3,11,15)-