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

We report here the rational design, synthesis and structural character ization in the solid state and in solution of the most potent and sele ctive peptide-based Neurokinin A (NKA) antagonist, thus far described. We predicted the bioactive conformation of the known NKA antagonist c yclo(-Met(1)-Gln(2)-Trp(3)-Phe(4)-Gly(5)-Leu(6)-) by comparison with t he known structures of other cyclohexapeptides. On this basis we desig ned a highly constrained peptide molecule corresponding to a bicyclic hexapeptide containing two rings of 14 atoms, namely Met(1)-Asp(2)-Trp (3)-Phe(4)-Dap(5)-Leu(6)-)cyclo(2 beta-5 beta). It was synthesized eff iciently, using a combined solution and solid phase strategy. We fully characterized this molecule in the solid state by X-ray diffraction a nd we show that it adopts an almost identical conformation in acetonit rile solution by NMR spectroscopy. This structure fully confirms our h ypothetical model. Its structure and conformational rigidity in soluti on explain the high potency and selectivity and the resistance to prot eolytic degradation. Therefore the structural requirements for NKA ant agonistic activity are clarified.