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[摘要]：The NK3 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 NK3 receptor antagonists using a virtual screening protocol of similarity analysis. The lead compound for this study was the potent NK3 antagonist talnetant. Compounds of the guillotine 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 NK3 receptor as well as to inhibit senktide-induced calcium responses in cells expressing the human NK3 receptor. Two novel compounds were identified that inhibited NK3 receptor agonist binding, with potencies in the nM range and antagonized NK3 receptor-mediated increases in intracellular calcium. These results demonstrate the utility of similarity analysis in identifying novel antagonist ligands for neuropeptide receptors. |
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