Key result
Replacement of the Tyr9 residue in P5U and urantide led to novel UT receptor superagonists with pEC50 values at least 1.4 log higher than P5U, and pure antagonists.
Effect estimate: pEC50 values at least 1.4 log higher than that of 1
The discovery of novel potent UT receptor ligands provides new tools to characterize the urotensinergic system in human physiopathology.
We have optimized 1 (P5U) and urantide, two important ligands at the h-UT receptor, designing several analogues by the exchange of the Tyr9 residue with different unnatural aromatic amino acids. This study allowed us to discover novel ligands with improved activity. In particular, the replacement of the Tyr9 residue by (pCN)Phe or (pNO2)Phe within the urantide sequence led to compounds 13 (UPG-83) and 15 (UPG-95), respectively, which showed pure antagonist activity toward UT receptor in a rat aorta bioassay. More interestingly, the replacement of the Tyr9 in 1 sequence with the Btz or the (3,4-Cl)Phe residues led to superagonists 6 (UPG-100) and 10 (UPG-92) with pEC50 values at least 1.4 log higher than that of 1, being the most potent UT agonists discovered to date. Compounds 10 and 13 showed also a good stability in a serum proteolytic assay. These ligands represent new useful tools to further characterize the urotensinergic system in human physiopathology.
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Carotenuto et al. (2014) studied this question. P5U and urantide analogues (compounds 6, 10, 13, 15) vs. P5U and urantide was evaluated on UT receptor activity (antagonist/agonist activity in rat aorta bioassay and pEC50) (pEC50 values at least 1.4 log higher than that of 1). Replacement of the Tyr9 residue in P5U and urantide led to novel UT receptor superagonists with pEC50 values at least 1.4 log higher than P5U, and pure antagonists.
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