title: Identification of a critical residue in the transmembrane domain 2 of tachykinin neurokinin 3 receptor affecting the dissociation kinetics and antagonism mode of osanetant (SR 142801) and piperidine-based structures.
abstract: In this study, we show that compound 3 (osanetant) binds with a pseudoirreversible, apparent noncompetitive mode of antagonism at the guinea pig NK(3), while it behaves competitively at the human NK(3). This difference is caused by a slower dissociation rate of compound 3 at the guinea pig NK(3) compared to human NK(3). The only amino acid difference between the human and guinea pig NK(3) in the binding site (Thr139(2.58) in human, corresponding to Ala114(2.58) in guinea pig) has been shown to be responsible for the different behavior. Compound 1 (talnetant), however, behaves competitively at both receptors. Using these data, 3D homology modeling, and site-directed mutagenesis, a model has been developed to predict the mode of antagonism of NK(3) antagonists based on their binding mode. This model was successfully used to predict the mode of antagonism of compounds of another chemical series including piperidine-based structures at human and guinea pig NK(3).
authors.affiliation: Discovery Research CNS, F. Hoffmann-La Roche Ltd., PRDN, Building 69/333, CH-4070 Basel, Switzerland. parichehr.malherbe@roche.com
authors.forename: Pari
authors.initials: P
authors.lastname: Malherbe
authors.forename: Claudia
authors.initials: C
authors.lastname: Kratzeisen
authors.forename: Anne
authors.initials: A
authors.lastname: Marcuz
authors.forename: Marie-Thérèse
authors.initials: MT
authors.lastname: Zenner
authors.forename: Matthias H
authors.initials: MH
authors.lastname: Nettekoven
authors.forename: Hasane
authors.initials: H
authors.lastname: Ratni
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Wettstein
authors.forename: Caterina
authors.initials: C
authors.lastname: Bissantz
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002417:Cattle; D002460:Cell Line; D002462:Cell Membrane; D004285:Dogs; D006168:Guinea Pigs; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D007553:Isotope Labeling; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010880:Piperidines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D051381:Rats; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D014316:Tritium / Q000737:chemistry
chemical_list: D007295:Inositol Phosphates; D010880:Piperidines; D018042:Receptors, Neurokinin-3; D014316:Tritium; C032727:piperidine; C091554:SR 142801