| Identification of Small Molecule Antagonists of the Human MRG-X1 Receptor |
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Presentation: 3B01 Session: Target Biology & Screening: GPCRsPriya Kunapuli, Seungtaek Lee, Wei Zheng, Melissa Alberts, Oleg Kornienko, Rebecca Mull and Berta Strulovici, Merck & Co. Presenting Author: Priya Kunapuli, Merck & Co. - U.S.A. The recently identified MRG-X1 receptor, located in sensory neurons, has been implicated in pain perception. Antagonists of this class of receptors are postulated to be useful analgesics. Towards this end, single cell clones expressing functional receptors were developed using the β-lactamase (BLA) reporter gene technology and fluorescence-activated cell sorting. Ultra high throughput screening of ~1 million compounds in a 1.8µl cell-based assay was conducted in a 3456-well plate format. Cellular trafficking of activated receptors, assessed by a fluorescence-based cell imaging assay using automated confocal microscopy, was used to further validate the mechanism of action of compounds with confirmed activity in the second messenger assay. The 2,3-disubstituted azabicyclo-octanes, appear to be relatively specific and potent competitive antagonists at the human MRG-X1 receptors. Structure-activity relationship reveals that within this class, the diphenylmethyl moiety is constant at the 2-substituent, while the 3-substituent is directly correlated with the antagonist activity. |