Importance of secondary structure for endothelin binding and functional activity.
ET-1[16-Phe] and ET-1[12-Pro] were prepared in order to investigate the importance of secondary structure of ET-1 for receptor binding and function. ET-1[16-Phe] displayed the greatest binding and contractile potency of the ET-analogs tested in rabbit pulmonary artery, rat aorta, and rat left atria. ET-1[12-Pro] also exhibited low nanomolar binding in these tissues but showed less contractile activity than ET-1[16-Phe] or ET-1. The results indicate that the helical region between residues Lys9 and Cys15 of ET-1 is not critical for receptor binding and functional activity. However, replacement of His16 with Phe altered the charge characteristics of the C-terminal region of ET-1 producing the most potent ET-1 analog yet reported.
Panek
R L
RL
Department of Pharmacology, Warner-Lambert Company, Ann Arbor, Michigan 48105.
Major
T C
TC
Taylor
D G
DG
Hingorani
G P
GP
Dunbar
J B
JB
Doherty
A M
AM
Rapundalo
S T
ST
D000818:Animals; D001011:Aorta / Q000187:drug effects; D001158:Arteries / Q000187:drug effects*; D001665:Binding Sites; D019332:Endothelin-1 / Q000031:analogs & derivatives; D016232:Endothelins / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D006325:Heart Atria / Q000187:drug effects*; D008968:Molecular Conformation; D009119:Muscle Contraction / Q000187:drug effects*; D011651:Pulmonary Artery / Q000187:drug effects; D011817:Rabbits; D013329:Structure-Activity Relationship
D019332:Endothelin-1; D016232:Endothelins; C073614:endothelin-1, Phe(16)-; C073615:endothelin-1, Pro(12)-