Structure-activity relationship for ETB agonism in truncated endothelin-1 analogs.
The essential part of the ETB-selective agonist N-acetyl-GluAlaValTyrPheAlaHisLeuAspIleIleTrp (N-Ac-4AlaET-1(10-21)) for ETB agonism was studied by single amino acid replacement. Single L-alanine substitutions at positions 14, 17, 20 and 21 and the corresponding D-amino acid substitutions at positions 14 and 16-21 resulted in remarkable decreases in ETB binding activity. Furthermore, these analogs elicited endothelium-dependent vasorelaxation in parallel with ETB binding activity. These data indicate that the amino acid residues of Phe14, Leu17, Ile20 and Trp21 and the backbone structure at Phe14 and His16-Trp21 in ET-1 are important for ETB agonism.
Saeki
T
T
Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Japan.
Ihara
M
M
Fukuroda
T
T
Yano
M
M
D000409:Alanine / Q000737:chemistry*; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002851:Chromatography, High Pressure Liquid; D016232:Endothelins / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000502:physiology; D066298:In Vitro Techniques; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D017466:Receptors, Endothelin / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013552:Swine; D014664:Vasodilation / Q000187:drug effects
D016232:Endothelins; D017466:Receptors, Endothelin; D000409:Alanine