SOLUTION CONFORMATION BY NMR AND MOLECULAR MODELING OF 3 SULFIDE-FREESOMATOSTATIN OCTAPEPTIDE ANALOGS COMPARED TO ANGIOPEPTIN

The conformation in dimethylsulfoxide of the somatostatin derivative a ngiopeptin and of three disulfide-free analogs was estimated by two-di mensional nuclear magnetic resonance spectroscopy at room temperature. The resulting 3D molecular graphics were compared and shown to reflec t the observed differences in the inhibition of restenosis after rat a orta balloon injury by these octapeptide inhibitors. Angiopeptin and i ts active analog 2 displayed a relatively rigid conformation of the cy clic hexapeptide backbone due to the presence of two well-defined hydr ogen bonds, further stabilized by a third hydrogen bond outside the ri ng. No such constraints were detected for the two biologically inactiv e analogs, which, compared to 2, had a two-atom longer or shorter hexa peptide ring. The well-defined structure of compound 2 may serve as an improved pharmacophore for this new class of drugs.