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.

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Malherbe P, Kratzeisen C, Marcuz A, Zenner MT, Nettekoven MH, Ratni H, Wettstein JG, Bissantz C

J Med Chem. 2009 Nov 26;52(22):7103-12. doi: 10.1021/jm900948q.

PubMed ID

19817444 [ View in PubMed

]

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).

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Osanetant	Neuromedin-K receptor	Ki (nM)	0.5	N/A	N/A	Details
Osanetant	Neuromedin-K receptor	Kd (nM)	0.22	N/A	N/A	Details
Osanetant	Neuromedin-K receptor	Kd (nM)	0.2	N/A	N/A	Details
Osanetant	Neuromedin-K receptor	Kd (nM)	18.62	N/A	N/A	Details
Talnetant	Neuromedin-K receptor	Ki (nM)	3	N/A	N/A	Details
Talnetant	Neuromedin-K receptor	Kd (nM)	5.75	N/A	N/A	Details