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-B

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• 作者：Pari Malherbe ; Claudia Kratzeisen ; Anne Marcuz ; Marie-Thrse Zenner ; Matthias H. Nettekoven ; Hasane Ratni ; Joseph G. Wettstein ; Caterina Bissantz
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：November 26, 2009
• 年：2009
• 卷：52
• 期：22
• 页码：7103-7112
• 全文大小：1081K
• 年卷期：v.52,no.22(November 26, 2009)
• ISSN：1520-4804

文摘

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 (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 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.