Rational design of high affinity tachykinin NK2 receptor antagonists.

Abstract The rational discovery of a high affinity NK 2 receptor antagonist is described utilizing a general strategy for peptoid design. The contribution to NK 2 receptor binding affinity for each amino acid of the hexapeptide ‘inimum fragment’: Leu-Met-Gln-Trp-Phe-GlyNH 2 ( 8c ), was examined by preparing derivatives where each amino acid in turn was replaced with Ala in an ‘alanine scan’. The results from this study indicated the primary importance of the Trp and Phe side-chain for binding and led to the observation that Z-Trp-PheNH 2 ( 9a ) is a micromolar affinity NK 2 receptor dipeptide lead. Further exploration of structure-affinity via conformationally restricted analogues and N- and C-terminus modifications gave a selective, nanomolar affinity NK 2 receptor antagonist, (2,3di-CH 3 OPh)CH 2 OCO( S )Trp( S )α-MePheGlyNH 2 , PD 147714 ( 19 ) with an K i = 1.4 nM (hamster urinary bladder membranes and using [ 125 I]-iodohistidyl-NKA (0.1 nM) as the radioligand).