Discovery of Potent Agonists for the Predominant Variant of the Orphan 
MAS-Related G Protein-Coupled Receptor X4 (MRGPRX4)

Marx, Daniel; Alnouri, Mohamad Wessam; Clemens, Sophie; Gedschold, Robin; Riedel, Yvonne; Al Hamwi, Ghazl; Pillaiyar, Thanigaimalai; Hockemeyer, Jorg; Namasivayam, Vigneshwaran; Mueller, Christa E.

doi:10.1021/acs.jmedchem.3c01013

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Discovery of Potent Agonists for the Predominant Variant of the Orphan MAS-Related G Protein-Coupled Receptor X4 (MRGPRX4)

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Alnouri, Mohamad Wessam
Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Citation

Marx, D., Alnouri, M. W., Clemens, S., Gedschold, R., Riedel, Y., Al Hamwi, G., et al. (2023). Discovery of Potent Agonists for the Predominant Variant of the Orphan MAS-Related G Protein-Coupled Receptor X4 (MRGPRX4). JOURNAL OF MEDICINAL CHEMISTRY, 66(23), 15674-15698. doi:10.1021/acs.jmedchem.3c01013.

Cite as: https://hdl.handle.net/21.11116/0000-000E-471E-2

Abstract

The MAS-related G(q) protein-coupled receptor X4 (MRGPRX4) is poorly investigated. MRGPRX4 has been proposed to be involved in pain transmission, itch, inflammation, wound healing, and cancer. However, so far only a few moderately potent, nonselective MRGPRX4 agonists have been described, most of which appear to preferably activate the minor receptor variant MRGPRX4-83L but not the main variant 83S. In the present study, we discovered a xanthine derivative bearing a phosphate substituent that activates the main variant of MRGPRX4. Optimization resulted in analogs with high potency and metabolic stability. The best compounds of the present series include 8-(m-methoxyphenethyl)-1-propargylxanthine substituted with a butyl linker in the 3-position containing a terminal phosphonate (30d, PSB-22034, EC50 Ca2+ assay/beta-arrestin assay, 11.2 nM/32.0 nM) and its N7-methyl derivative 31d (PSB-22040, EC50, 19.2/30.0 nM) showing high selectivity versus all other MRGPRX subtypes. They present promising tool compounds for exploring the potential of MRGPRX4 as a future drug target.