Discovery of new antagonists aimed at discriminating UII and URP ‐mediated biological activities: insight into UII and URP receptor activation

Background and Purpose Recent evidence suggested that urotensin II ( UII ) and its paralog peptide UII ‐related peptide ( URP ) might exert common but also divergent physiological actions. Unfortunately, none of the existing antagonists were designed to discriminate specific UII ‐ or URP ‐associated actions, and our understanding, on how these two endogenous peptides can trigger different, but also common responses, is limited. Experimental Approach Ex vivo rat and monkey aortic ring contraction as well as dissociation kinetics studies using transfected CHO cells expressing the human urotensin ( UT ) receptors were used in this study. Key Results Ex vivo rat and monkey aortic ring contraction studies revealed the propensity of [ Pep 4 ] URP to decrease the maximal response of human UII ( hUII ) without any significant change in potency, whereas no effect was noticeable on the URP ‐induced vasoconstriction. Dissociation experiments demonstrated the ability of [ Pep 4 ] URP to increase the dissociation rate of hUII , but not URP . Surprisingly, URP , an equipotent UII paralog, was also able to accelerate the dissociation rate of membrane‐bound 125 I‐hUII , whereas hUII had no noticeable effect on URP dissociation kinetics. Further experiments suggested that an interaction between the glutamic residue at position 1 of hUII and the UT receptor seems to be critical to induce conformational changes associated with agonistic activation. Finally, we demonstrated that the N ‐terminal domain of the rat UII isoform was able to act as a specific antagonist of the URP ‐associated actions. Conclusion Such compounds, that is [ Pep 4 ] URP and rUII (1–7), should prove to be useful as new pharmacological tools to decipher the specific role of UII and URP   in vitro but also in vivo .