Design, synthesis, conformational analysis, and biological studies of urotensin-II lactam analogues.
Human urotensin II (hU-II; H-Glu-Thr-Pro-Asp-cyclo[Cys-Phe-Trp-Lys-Tyr-Cys]-Val-OH) is a disulfide bridged undecapeptide recently identified as the ligand of an orphan G protein-coupled receptor. hU-II has been described as the most potent vasoconstrictor compound identified to date. With the aim of replacing the disulfide bridge by a chemically more stable moiety, we have synthesized and tested a series of lactam analogues of hU-II minimum active fragment, that is hU-II(4-11). The contractile activity of the synthetic analogues on the rat isolated thoracic aorta was found to be dependent upon the dimension of the lactam bridge. The most active peptide, H-Asp-cyclo[Orn-Phe-Trp-Lys-Tyr-Asp]-Val-OH (3), is approximately 2 logs less potent than hU-II (pD(2)=6.3 vs 8.4). A conformational analysis in solution of the active peptide 3, one of the inactive analogues, and hU-II was performed, using NMR and molecular modelling techniques. A superposition of the calculated structures of hU-II and 3 clearly shows that three out of four key residues (i.e., Phe(6), Lys(8) and Tyr(9)) maintain the same side- chain orientation, while the fourth one, Trp(7), cannot be superimposed. This observation could explain the reduced biological activity of the synthetic analogue.
Grieco
Paolo
P
Department of Pharmaceutical and Toxicological Chemistry, University of Naples Federico II, Naples, Italy.
Carotenuto
Alfonso
A
Patacchini
Riccardo
R
Maggi
Carlo A
CA
Novellino
Ettore
E
Rovero
Paolo
P
D000818:Animals; D001011:Aorta / Q000187:drug effects; D015195:Drug Design; D004355:Drug Stability; D006801:Humans; D007769:Lactams / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D019906:Nuclear Magnetic Resonance, Biomolecular; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D014579:Urotensins / Q000737:chemistry* / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D007769:Lactams; D010456:Peptides, Cyclic; D014579:Urotensins; D014662:Vasoconstrictor Agents; C029677:urotensin II