Johns Hopkins Drug Discovery - Project - MAS-Related GPCR X1
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MAS-Related GPR X1 (MRGPRX1)

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Chemistry in action

Mas-related gene (Mrg) receptors, also known as sensory-neuron specific receptors (SNSRs), constitute a family of G-protein-coupled receptors that are implicated in nociception. A subset of these receptors is expressed specifically in the DRG sensory neurons, implicating a role in modulating nociceptive signaling.1, 2,3 In collaboration with Dr. Xinzhong Dong, we have shown that JHU-58, a small molecule agonist of rat MrgC and mouse MrgC11, attenuated neuropathic pain in both rats and mice but not in KO mice lacking a cluster of Mrg genes including MrgC11.4-6  We are currently developing positive allosteric modulators (PAMs) of MRGPRX1, a member of human Mrg receptors, as analgesic agents to treat patients suffering from neuropathic pain.

 

REFERENCES

  1. Dong X, Han S, Zylka MJ, Simon MI, Anderson DJ. A diverse family of GPCRs expressed in specific subsets of nociceptive sensory neurons. Cell. 2001;106(5):619-32. [PubMed]
  2. Guan Y, Liu Q, Tang Z, Raja SN, Anderson DJ, Dong X. Mas-related G-protein-coupled receptors inhibit pathological pain in mice. Proc Natl Acad Sci U S A. 2010;107(36):15933-8. [PubMed]
  3. Li Z, Tseng P, Tiwari V, Xu Q, He SQ, Wang Y, Zheng Q, Han L, Wu Z, Blobaum AL, Cui Y, Tiwari V, Sun S, Cheng Y, Huang-Lionnet JH, Geng Y, Xiao B, Peng J, Hopkins C, Raja SN, Guan Y, Dong X.  “Targeting human Mas-related G protein-coupled receptor X1 to inhibit persistent pain.” Proc Natl Acad Sci USA, 2017, 114, E1996-E2005. [PubMed]
  4. He SQ, Li Z, Chu YX, Han L, Xu Q, Li M, Yang F, Liu Q, Tang Z, Wang Y, Hin N, Tsukamoto T, Slusher B, Tiwari V, Shechter R, Wei F, Raja SN, Dong X, Guan Y. MrgC agonism at central terminals of primary sensory neurons inhibits neuropathic pain. Pain. 2014;155(3):534-44. [PubMed].
  5. Hin N, Alt J, Zimmermann SC, Delahanty G, Ferraris DV, Rojas C, Li F, Liu Q, Dong X, Slusher BS, Tsukamoto T. Peptidomimetics of Arg-Phe-NH2 as small molecule agonists of Mas-related gene C (MrgC) receptors. Bioorg Med Chem. 2014;22(21):5831-7. [PubMed]
  6. Li Z, He SQ, Xu Q, Yang F, Tiwari V, Liu Q, Tang Z, Han L, Chu YX, Wang Y, Hin N, Tsukamoto T, Slusher B, Guan X, Wei F, Raja SN, Dong X, Guan Y. Activation of MrgC receptor inhibits N-type calcium channels in small-diameter primary sensory neurons in mice. Pain. 2014;155(8):1613-21. [PubMed]