Structure-activity relationship of analogues of endothelin-1: dissociation of hypotensive and pressor actions.
The structural requirements of endothelin-1 to evoke depressor and pressor responses were studied in conscious rats. Formylation of the C-terminal Trp eliminated the depressor but not the pressor activity of endothelin-1. Oxidation of Met7 in this analogue restored the hypotensive activity. Destruction of the Cys1-Cys15 disulphide bridge led to a weak agonist with both depressor and pressor activities. Formylation of Trp21 in this analogue resulted in a complete loss of biological activity. These results indicate that Met7 and the indole moiety of Trp21 are important for the expression of the depressor activity of endothelin-1 whereas the intramolecular loop structure is less important. The results also provide further evidence that the depressor and pressor effects of endothelin-1 are mediated through different receptors.
Filep
J G
JG
Department of Pharmacology, Faculty of Medicine, University of Sherbrooke, Canada.
Rousseau
A
A
Fournier
A
A
Sirois
P
P
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D016232:Endothelins / Q000737:chemistry / Q000494:pharmacology*; D007022:Hypotension / Q000139:chemically induced*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
D016232:Endothelins