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

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

  • J Med Chem. 2023 Nov 15. doi: 10.1021/acs.jmedchem.3c01013.
Daniel Marx 1 2,  Mohamed Wessam Alnouri 1 2,  Sophie Clemens 1 2,  Robin Gedschold 1 2,  Yvonne Riedel 1 2,  Ghazl Al Hamwi 1 2,  Thanigaimalai Pillaiyar 1 2,  Jörg Hockemeyer 1 2,  Vigneshwaran Namasivayam 1 2,  Christa E Müller 1 2
Affiliations

Affiliations

  • 1 Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
  • 2 PharmaCenter Bonn, University of Bonn, Brühler Straße 7, D-53121 Bonn, Germany.
PMID: 37967029 DOI: 10.1021/acs.jmedchem.3c01013
Abstract

The MAS-related Gq 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/β-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.

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