title: Molecular basis for the species selectivity of the substance P antagonist CP-96,345.
abstract: The non-peptide substance P (SP) antagonist CP-96,345 has a 90-fold selectivity for the human neurokinin-1 (NK-1) or SP receptor over the rat NK-1 receptor, while the agonist SP shows no such selectivity. The cloned NK-1 receptors from these two species have primary protein structures that differ in only 22 of 407 residues. Wild type, chimeric, and point-mutated NK-1 receptors have been created and functionally expressed to understand the structural basis of this species selectivity. Residue 290 in the seventh putative membrane-spanning region is responsible for 20-fold of the affinity difference seen for CP-96,345 between the rat and human NK-1 receptors. Residues in the second extracellular loop and in membrane-spanning region six contribute the additional 3-5-fold of the species difference. The direct or indirect action of these residues with this nonpeptidic antagonist is discussed. This study serves to emphasize the need for species-appropriate in vitro models for the screening of antagonists in the search for therapeutics, and provides useful information to model nonpeptidic antagonist interactions with peptide hormone receptors.
authors.affiliation: Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri 63110.
authors.forename: B S
authors.initials: BS
authors.lastname: Sachais
authors.forename: R M
authors.initials: RM
authors.lastname: Snider
authors.forename: J A
authors.initials: JA
authors.lastname: Lowe
authors.forename: J E
authors.initials: JE
authors.lastname: Krause
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001713:Biphenyl Compounds / Q000737:chemistry*; D006801:Humans; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D051381:Rats; D018040:Receptors, Neurokinin-1; D017981:Receptors, Neurotransmitter / Q000737:chemistry / Q000187:drug effects*; D011993:Recombinant Fusion Proteins; D013329:Structure-Activity Relationship; D013373:Substance P / Q000037:antagonists & inhibitors*
chemical_list: D001713:Biphenyl Compounds; D009838:Oligodeoxyribonucleotides; D018040:Receptors, Neurokinin-1; D017981:Receptors, Neurotransmitter; D011993:Recombinant Fusion Proteins; D013373:Substance P; C066892:CP 96345