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

• Published in: Journal of medicinal chemistry Vol. 52; no. 22; pp. 7103 - 7112
• Main Authors: Malherbe, Pari, Kratzeisen, Claudia, Marcuz, Anne, Zenner, Marie-Thérèse, Nettekoven, Matthias H, Ratni, Hasane, Wettstein, Joseph G, Bissantz, Caterina
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 26.11.2009; Amer Chemical Soc
• Subjects: Amino Acid Sequence; Animals; Biological and medical sciences; Cattle; Cell Line; Cell Membrane; Chemistry, Medicinal; Dogs; Guinea Pigs; Humans; Inositol Phosphates - metabolism; Isotope Labeling; Kinetics; Life Sciences & Biomedicine; Medical sciences; Models, Molecular; Molecular Conformation; Molecular Sequence Data; Mutagenesis, Site-Directed; Mutation; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Piperidines - chemistry; Piperidines - metabolism; Piperidines - pharmacology; Protein Structure, Tertiary; Rats; Receptors, Neurokinin-3 - antagonists & inhibitors; Receptors, Neurokinin-3 - chemistry; Receptors, Neurokinin-3 - genetics; Receptors, Neurokinin-3 - metabolism; Reproducibility of Results; Science & Technology; Tritium - chemistry; NK3 RECEPTOR; BINDING-KINETICS; RAT; PHARMACOLOGICAL CHARACTERIZATION; SCHIZOPHRENIA; CENTRAL-NERVOUS-SYSTEM; GUINEA-PIG; SB 223412; TALNETANT; DRUG-ACTION; Human; Ligand binding; Rodentia; Benzene derivatives; In vitro; Modeling; Vertebrata; Mammalia; Guinea pig; Structure activity relation; Chlorine Organic compounds; Animal; Piperidine derivatives; Molecular model; NK3 Tachykinin receptor; Binding mode; Carboxamide; Benzamide derivatives; Fluorine Organic compounds; Antagonist; Kinetics; Osanetant; Tachykinin; Comparative study
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/jm900948q

In this study, we show that compound 3 (osanetant) binds with a pseudoirreversible, apparent noncompetitive mode of antagonism at the guinea pig NK3, while it behaves competitively at the human NK3. This difference is caused by a slower dissociation rate of compound 3 at the guinea pig NK3 compared to human NK3. The only amino acid difference between the human and guinea pig NK3 in the binding site (Thr1392.58 in human, corresponding to Ala1142.58 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 NK3 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 NK3.