Structure determination and by-product profile of the NK2 receptor antagonist nepadutant, a bicyclic glycopeptide

We have synthesized and fully characterized the NK2 receptor antagonist nep adutant and its by-products using nuclear magnetic resonance (NMR) and rest rained molecular dynamics. The agent consists of an active bicyclic hexapep tide combined with a sugar residue. Analysis of the high-performance liquid chromatogram and the mass spectroscopy spectra yields traces of three by-p roducts with the same molecular weight as the main product, The conformatio n of the molecules in the bicyclic hexapeptide segment, the active region, is well defined, whereas the sugar moiety is disordered, For the peptide re gion of nepadutant and all of its by-products, the NMR observables can be d escribed bgl a single backbone conformation, more specifically a betaI, bet a II-turn arrangement. The active dipeptide unit Trp-Phe occupies the i+1 a nd i+2 position of a beta1-turn, The byproduct profile is characterized bg different forms of sugars which are! caused mainly by isomerization in the process of ring opening. (C) 2001 Federation of European Biochemical Societ ies. Published by Elsevier Science B.V, All rights reserved.