title: Two related neurokinin-1 receptor antagonists have overlapping but different binding sites.
abstract: The neuropeptide substance P binds to the G protein-coupled neurokinin-1 (NK-1) receptor and elicits cellular responses thought to be involved in pain, neurogenic inflammation, vasodilatation, and plasma exudation. 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 binding site for these nonpeptide antagonists lies within the bundle created by transmembrane domains IV-VII of the receptor. This current investigation employs site directed mutagenesis of the NK-1 receptor to compare the binding site of CP-96,345 with that of a related compound CP-99,994. The data demonstrate that while both compounds appear to bind within the transmembrane domain bundle, the contribution of individual amino acid residues to the binding of each compound differs.
authors.affiliation: Department of Allergy, Schering-Plough Research Institute, Kenilworth, NJ 07033, USA. scott.greenfeder@spcorp.com
authors.forename: S
authors.initials: S
authors.lastname: Greenfeder
authors.forename: B
authors.initials: B
authors.lastname: Cheewatrakoolpong
authors.forename: J
authors.initials: J
authors.lastname: Anthes
authors.forename: M
authors.initials: M
authors.lastname: Billah
authors.forename: R W
authors.initials: RW
authors.lastname: Egan
authors.forename: J E
authors.initials: JE
authors.lastname: Brown
authors.forename: N J
authors.initials: NJ
authors.lastname: Murgolo
mesh_terms: D000818:Animals; D001665:Binding Sites; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000378:metabolism*; D019556:COS Cells; D006801:Humans; D006993:Hypnotics and Sedatives / Q000138:chemical synthesis* / Q000378:metabolism*; D008956:Models, Chemical; D016297:Mutagenesis, Site-Directed; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines / Q000138:chemical synthesis* / Q000378:metabolism*; D018040:Receptors, Neurokinin-1 / Q000235:genetics; D013237:Stereoisomerism; D013373:Substance P / Q000378:metabolism
chemical_list: D001713:Biphenyl Compounds; D006993:Hypnotics and Sedatives; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D018040:Receptors, Neurokinin-1; C080755:3-(2-methoxybenzylamino)-2-phenylpiperidine; D013373:Substance P; C066892:CP 96345