Virtual screening to identify novel antagonists for the G protein-coupled NK3 receptor.

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Geldenhuys WJ, Kuzenko SR, Simmons MA

Virtual screening to identify novel antagonists for the G protein-coupled NK3 receptor.

J Med Chem. 2010 Nov 25;53(22):8080-8. doi: 10.1021/jm1010012. Epub 2010 Nov 3.

PubMed ID
21047106 [ View in PubMed
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Abstract

The NK(3) subtype of tachykinin receptor is a G protein-coupled receptor that is a potential therapeutic target for several neurological diseases, including schizophrenia. In this study, we have screened compound databases for novel NK(3) receptor antagonists using a virtual screening protocol of similarity analysis. The lead compound for this study was the potent NK(3) antagonist talnetant. Compounds of the quinoline type found in the virtual screen were additionally evaluated in a comparative molecular field analysis model to predict activity a priori to testing in vitro. Selected members of this latter set were tested for their ability to inhibit ligand binding to the NK(3) receptor as well as to inhibit senktide-induced calcium responses in cells expressing the human NK(3) receptor. Two novel compounds were identified that inhibited NK(3) receptor agonist binding, with potencies in the nM range and antagonized NK(3) receptor-mediated increases in intracellular calcium. These results demonstrate the utility of similarity analysis in identifying novel antagonist ligands for neuropeptide receptors.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
TalnetantNeuromedin-K receptorIC 50 (nM)6.1N/AN/ADetails
TalnetantNeuromedin-K receptorIC 50 (nM)16.6N/AN/ADetails
TalnetantNeuromedin-K receptorKi (nM)2.51N/AN/ADetails