Structural Requirement for Antagonist Activity at Tachykinin NK2 Receptor in a Series of Bicyclic Hexapeptides

The authors describe here the conformational and configurational requirements for the high affinity interaction of MEN 10627 with tachykinin NK2 receptor. The remarkable differences in the antagonist potencies shown by the peptides described herein are strictly related to their different structures. Less active compdounds are characterized by different orientations of the amino acid side chains. In the homochiral sequences, the bridge residues Asp2 and Dap5 are located in the i and i+3 positions of two b-turns, while in the heterochiral sequences the bridge residues occupy the i+2 positions of two b-turns. This shift of b-turn corner positions determines a completely different molecular shape and a dramatic drop in biological activity.