Identification of small molecule antagonists of the human mas-related gene-X1 receptor

Analytical Biochemistry
Priya KunapuliBerta Strulovici

Abstract

The recently identified mas-related-gene (MRG) family of receptors, located primarily in sensory neurons of the dorsal root ganglion, has been implicated in the perception of pain. Thus, antagonists of this class of receptors have been postulated to be useful analgesics. Toward this end, we developed a cell-based beta-lactamase (BLA) reporter gene assay to identify small molecule antagonists of the human MRG-X1 receptor from a library of compounds. Single-cell clones expressing functional receptors were selected using the BLA reporter gene technology. The EC50 for the MRG agonist peptide, BAM15, appeared to be comparable between the BLA assay and the intracellular Ca2+ transient assays in these cells. Ultra high-throughput screening of approximately 1 million compounds in a 1.8-microl cell-based BLA reporter gene assay was conducted in a 3456-well plate format. Compounds exhibiting potential antagonist profile in the BLA assay were confirmed in the second messenger Ca2+ transient assay. A cell-based receptor trafficking assay was used to further validate the mechanism of action of these compounds. Several classes of compounds, particularly the 2,3-disubstituted azabicyclo-octanes, appear to be relatively potent antagonists at t...Continue Reading

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Citations

Oct 12, 2010·Journal of Biomedicine & Biotechnology·Seena K AjitEdward J Kaftan
Oct 19, 2006·Current Opinion in Biotechnology·Moo-Yeal Lee, Jonathan S Dordick
May 29, 2014·Pharmacological Reviews·Hans Jürgen SolinskiAndreas Breit
Feb 24, 2019·Stem Cell Research & Therapy·Mingjun TangJian Ge
Sep 24, 2014·Pharmacological Reviews·Michael BaderRobson A Santos
Feb 23, 2017·Proceedings of the National Academy of Sciences of the United States of America·Zhe LiXinzhong Dong
Apr 1, 2021·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Hayley McMillanIkhlas El Karim
Jan 17, 2009·Journal of Medicinal Chemistry·Berthold WroblowskiWilliam J Coates

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