Structure determination and by-product profile of the NK 2 receptor antagonist nepadutant, a bicyclic glycopeptide

Abstract

We have synthesized and fully characterized the NK 2 receptor antagonist nepadutant and its by-products using nuclear magnetic resonance (NMR) and restrained molecular dynamics. The agent consists of an active bicyclic hexapeptide combined with a sugar residue. Analysis of the high-performance liquid chromatogram and the mass spectroscopy spectra yields traces of three by-products with the same molecular weight as the main product. The conformation of the molecules in the bicyclic hexapeptide segment, the active region, is well defined, whereas the sugar moiety is disordered. For the peptide region of nepadutant and all of its by-products, the NMR observables can be described by a single backbone conformation, more specifically a βI, βII-turn arrangement. The active dipeptide unit Trp–Phe occupies the i+1 and i+2 position of a βI-turn. The by-product profile is characterized by different forms of sugars which are caused mainly by isomerization in the process of ring opening.