The vasoactive cyclic undecapeptide urotensin-II (U-II) has been identified as an endogenous ligand for the G-protein
coupled receptor now referred to as the UT receptor. The U-II/UT receptor system might be relevant for cardiovascular functions.
A structure-activity study of human U-II investigating 31 peptides in the rat aorta bioassay is reported. Ala- and D-scan
investigations indicated that the sequence Phe6-Trp7-Lys8-Tyr9 is essential for biological activity and that Lys8 and Tyr9 are
particularly important. These two residues were substituted with a series of coded and non-coded amino acids. These studies
demonstrated that the positive charge of the primary aliphatic amine at position 8 and its relative spatial orientation is crucial
for both receptor occupation and activation, while the only chemical requirement at position 9 is the presence of an aromatic
moiety. Moreover, this study led to the identification of UT receptor partial agonists (compounds 23 and 24) which can be used
as chemical templates for further investigations aimed at the identification of selective antagonists