Discovery of New Allosteric Modulators of the Urotensinergic System through Substitution of the Urotensin II-Related Peptide (URP) Phenylalanine Residue.

Urotensin II (UII) and urotensin II-related peptide (URP) are functionally selective, suggesting that these two hormones might play distinct physiological role through different interactions with their cognate receptor UT. Hypothesizing that the Phe ³ residue of URP, which is also present in UII, is a key-element of its specific UT activation, we evaluated the impact of its replacement by non-natural amino acids in URP. Each compound was evaluated for its ability to bind UT, induce rat aortic ring contraction, and activate G _q , G ₁₂ , and β-arrestin 1 signaling pathways. Such modifications impaired contractile efficacy, reflected by a reduced aptitude to activate G ₁₂ in URP but not in the truncated but equipotent UII _4-11 . Moreover, we have identified two structurally different UT modulators: [d-Phe(pI) ³ ]URP and [Bip ³ ]URP, which exert a probe-dependent action against UII and URP. These compounds should help us understand the specific roles of these hormones as well as guide further therapeutic development.