Endothelin-1 analogues substituted at both position 18 and 19: highly potent endothelin antagonists with no selectivity for either receptor subtype ETA or ETB.
Kikuchi T, Kubo K, Ohtaki T, Suzuki N, Asami T, Shimamoto N, Wakimasu M, Fujino M.
Novel endothelin-1 (ET-1) analogues which are highly potent endothelin antagonists at both receptor subtype ETA and ETB are reported. The replacement of Asp18 with the Thr18 and of Ile19 with a hydrophobic amino acid whose side-chain branches on the gamma-carbon such as Leu, cyclohexylalanine, and gamma-methylleucine (gamma-MeLeu) resulted in loss of or significantly decreased the biological activity of ET-1, while high affinity for the ETA (IC50 = 0.42-0.70 nM) and ETB (IC50 = 0.17-0.43 nM) receptor was retained. These compounds were shown to have high antagonist activities in ET-1-induced vasoconstriction of porcine coronary artery (pA2 7.4-7.7) and in Sarafotoxin S6c-induced vasoconstriction of rabbit pulmonary artery ([Thr18, gamma-MeLeu19]ET-1: pA2 8.4). Among these compounds, [Thr18, gamma-MeLeu19]ET-1 has the desirable characteristic of possessing no agonist activity at either receptor subtype.