P2Y14Receptor Antagonists Reverse Chronic Neuropathic Pain in a Mouse Model

Fatma Mufti, Young Hwan Jung, Luigino Antonio Giancotti, Jinha Yu, Zhoumou Chen, Ngan B. Phung, Kenneth A. Jacobson, Daniela Salvemini

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Eight P2Y14R antagonists, including three newly synthesized analogues, containing a naphthalene or phenyl-triazolyl scaffold were compared in a mouse model of chronic neuropathic pain (sciatic constriction). P2Y14R antagonists rapidly (≤30 min) reversed mechano-allodynia, with maximal effects typically within 1 h after injection. Two analogues (4-[4-(4-piperidinyl)phenyl]-7-[4-(trifluoromethyl)phenyl]-2-naphthalenecarboxylic acid 1 and N-acetyl analogue 4, 10 μmol/kg, i.p.) achieved complete pain reversal (100%) at 1 to 2 h, with relief evident up to 5 h for 4 (41%). A reversed triazole analogue 7 reached 87% maximal protection. Receptor affinity was determined using a fluorescent antagonist binding assay, indicating similar mouse and human P2Y14R affinity. The mP2Y14R affinity was only partially predictive of in vivo efficacy, suggesting the influence of pharmacokinetic factors. Thus P2Y14R is a potential therapeutic target for treating chronic pain.

Original languageEnglish
Pages (from-to)1281-1286
Number of pages6
JournalACS Medicinal Chemistry Letters
Volume11
Issue number6
DOIs
StatePublished - 11 Jun 2020

Keywords

  • G-protein-coupled receptor
  • P2Y receptor
  • antagonist
  • chronic neuropathic pain
  • mouse

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