Synthesis and conformational analysis of cyclic pentapeptide endothelin antagonists.
Two endothelin antagonists cyclo(D-Leu-D-Val-Pro-D-Asp-Trp) (IPI-147), and cyclo (D-Trp-D-Asp-Ac3c-D-Val-Leu) (IPI-725) have been synthetized. Their solution conformations have been studied in aqueous solution by NMR spectroscopy and dynamics simulation. Activity studies show that IPI-725 is a strong ETA antagonist, while IPI-147 is a weak ETA antagonist. Comparison of the solution conformations of these two ETA antagonists suggests that the difference in their activities results from their structural differences. IPI-147 contains a type II beta-turn with a hydrogen bond between NH of D-Val and the C = O of D-Asp. IPI-725, on the other hand, contains two turns, a type II beta-turn with a hydrogen bond between NH of D-Asp and C = O of D-Val, as well as a gamma'-turn with a hydrogen bond formed between D-Val NH and D-Asp carbonyl group. Therefore IPI-147 appears to be more flexible than IPI-725. Although both beta-turns contain the same residues, their orders in the turn are reversed. The beta-turn in IPI-725 is formed with D-Val:Leu:D-Trp:D-Asp, while in IPI-147, the beta-turn is formed with D-Asp:Trp:D-Leu:D-Val. The activities and solution conformations of IPI-147 and IPI-725 were also compared with BQ-123 [cyclo(D-Trp-D-Asp-Pro-D-Val-Leu)], a well characterized, highly potent endothelin antagonist.
Department of Chemistry, University of Kansas, Lawrence, USA.
M
M
Lin
M F
MF
Chan
V N
VN
Balaji
R S
RS
Castillo
C K
CK
Larive
D016232:Endothelins / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology*
D016232:Endothelins; D009842:Oligopeptides; D010456:Peptides, Cyclic; C103566:cyclo(leucyl-valyl-prolyl-aspartyl-tryptophan); C103567:cyclo(tryptophyl-aspartyl-acetyl(3)c-valyl-leucyl)