SYNTHESIS AND SOLUTION CONFORMATION OF C(D-TRP-D-CYS(SO3-NA-PRO-D-VAL-LEU), A POTENT ENDOTHELIN-A RECEPTOR ANTAGONIST())

The endothelin family of polypeptides are known to exert potent physio logical effects which include cardiovascular regulation. The solution conformation and dynamics Of c(D-Trp-D-Cys(SO3-Na+)-Pro-D-Val-Leu), a potent endothelin-A receptor-selective antagonist, were characterized in aqueous solution by NMR spectroscopy and molecular modeling. NMR-de rived conformational constraints were combined with computer-assisted molecular modeling using distance geometry calculations and energy min imization. The pentapeptide backbone is shown to adopt a single confor mation in solution comprising a type II beta-turn and an inverse gamma -turn, with each residue in the trans conformation. Molecular dynamics were e measurements and low-temperature studies, and indicate that th e peptide backbone is highly constrained with little conformational mo bility present. (C) Munksgaard 1993.