SYNTHESIS OF POTENT CYCLIC HEXAPEPTIDE NK-1 ANTAGONISTS - USE OF A MINILIBRARY IN TRANSFORMING A PEPTIDAL SOMATOSTATIN RECEPTOR-LIGAND INTOAN NK-1 RECEPTOR-LIGAND VIA A POLYVALENT PEPTIDOMIMETIC

The endogenous peptides somatostatin (SRIF) and substance P comprise v ery different structures. Although both bind G-protein-coupled recepto rs, the SRIF receptors (SSTR 1-5) recognize SRIF and related peptides which retain its beta-turn such as the potent cyclic hexapeptide SRIF agonist L-363,301 (6a), but not substance P. Conversely the NK-1 recep tor binds substance P but not the above ligands. In contrast, the beta -D-glucosides 1 and 2, designed to mimic the beta-turn Of 6a, bind bot h receptors. This observation led us to attempt the conversion of 6a i nto the first potent, selective cyclic hexapeptide ligand for the NK-1 receptor. To this end, we combined design with a minilibrary approach . The goal was accomplished with surprising ease, leading to the NK-1 receptor antagonist 9 (IC50 2.0 +/- 0.4 nM). This demonstrates that pe ptidomimetics, incorporating in this case the promiscuous beta-D-gluco se scaffold, can provide valuable clues about receptor similarities no t revealed by their endogenous ligands. In addition, this work suggest s that the use of libraries and rational design need not be mutually e xclusive approaches to lead discovery.