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

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Discovery of Potent Agonists for the Predominant Variant of the Orphan MAS-Related G Protein-Coupled Receptor X4 (MRGPRX4)
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-11-15 , 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}

Affiliation

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/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.

中文翻译：

孤儿 MAS 相关 G 蛋白偶联受体 X4 (MRGPRX4) 主要变体的有效激动剂的发现

MAS 相关的 G _q蛋白偶联受体 X4 (MRGPRX4) 的研究很少。 MRGPRX4 被认为与疼痛传递、瘙痒、炎症、伤口愈合和癌症有关。然而，到目前为止，仅描述了一些中等效力的非选择性 MRGPRX4 激动剂，其中大多数似乎优选激活次要受体变体 MRGPRX4-83L，但不激活主要变体 83S。在本研究中，我们发现了一种带有磷酸盐取代基的黄嘌呤衍生物，可以激活 MRGPRX4 的主要变体。优化产生了具有高效力和代谢稳定性的类似物。本系列中最好的化合物包括 8-(间甲氧基苯乙基)-1-炔丙基黄嘌呤，在 3 位被丁基连接体取代，含有末端膦酸酯 ( 30d ，PSB-22034，EC ₅₀ Ca ²⁺测定/β-arrestin测定，11.2 nM/32.0 nM) 及其 N7-甲基衍生物31d (PSB-22040，EC _50，19.2 /30.0 nM) 与所有其他 MRGPRX 亚型相比显示出高选择性。他们提出了有前景的工具化合物，用于探索 MRGPRX4 作为未来药物靶点的潜力。

更新日期：2023-11-15

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