2 RELATED NEUROKININ-1 RECEPTOR ANTAGONISTS HAVE OVERLAPPING BUT DIFFERENT BINDING-SITES

The neuropeptide substance P binds to the G protein-coupled neurokinin -l (NK-I) receptor and elicits cellular responses thought to be involv ed in pain, neurogenic inflammation, vasodilatation, and plasma exudat ion. Several small molecule nonpeptide antagonists of the substance P/ NK-1 receptor interaction have been developed. Mutational analysis of the receptor protein sequence has led to the conclusion that the bindi ng site for these nonpeptide antagonists lies within the bundle create d by transmembrane domains IV-VII of the receptor. This current invest igation employs site directed mutagenesis of the NK-1 receptor to comp are the binding site of CP-96,345 with that of a related compound CP-9 9,994. The data demonstrate that while both compounds appear to bind w ithin the transmembrane domain bundle, the contribution of individual amino acid residues to the binding of each compound differs. (C) 1998 Elsevier Science Ltd. All rights reserved.