DESIGN AND STRUCTURE OF A NOVEL NEUROKININ A RECEPTOR ANTAGONIST CYCLO(-MET(1)-ASP(2)-TRP(3)-PHE(4)-DAP(5)-LEU(6)-)CYCLO(2-BETA-5-BETA)

We report here the rational design, synthesis and structural characterization in the solid state and in solution of the most potent and selective peptide-based Neurokinin A (NKA) antagonist, thus far described. We predicted the bioactive conformation of the known NKA antagonist cyclo(-Met(1)-Gln(2)-Trp(3)-Phe(4)-Gly(5)-Leu(6)-) by comparison with the known structures of other cyclohexapeptides. On this basis we designed a highly constrained peptide molecule corresponding to a bicyclic hexapeptide containing two rings of 14 atoms, namely cyclo(-Met(1)-Asp(2)-Trp(3)-Phe(4)-Dap(5)-Leu(6)-)cyclo(2 beta-5 beta). It was synthesized efficiently, using a combined solution and solid phase strategy. We fully characterized this molecule in the solid state by X-ray diffraction and we show that it adopts an almost identical conformation in acetonitrile solution by NMR spectroscopy. This structure fully confirms our hypothetical model. Its structure and conformational rigidity in solution explain the high potency and selectivity and the resistance to proteolytic degradation. Therefore the structural requirements for NKA antagonistic activity are clarified.