STRUCTURE-ACTIVITY STUDIES OF THE C-TERMINAL SEGMENT OF STRUCTURALLY REDUCED ANALOGS OF ET-1

Structurally reduced analogues of endothelin-l (ET-1) were synthesized by linking via aminocaproic acid (Aca) the segment 3-11 of ET-1 to C- terminal fragments of various lengths [16-21, 17-21,..., 21]. Analogue s were studied in their linear or cyclic form in the absence or presen ce of a formyl group on the Trp(21) side-chain, and their biologic act ivities were tested using guinea pig lung parenchymal strips. The abse nce of the first disulfide bridge and the presence of the Aca spacer c aused a slight decrease in activity. The presence of His(16) is essent ial for the contractile activity of the monocyclic peptides. Formylati on of these monocyclic analogues did not modify this behavior. Similar ly, linear analogues carrying S-acetamidomethyl (Acm) functions and an Aca linker were still active. However, most formylated linear derivat ives were partial agonists, whereas the addition of His(16) caused a d ecrease in contractile activity. In these latter analogues, molecular modeling studies suggested that formylation produces different conform ations.