1. Academic Validation
  2. P2Y14 Receptor Antagonists Reverse Chronic Neuropathic Pain in a Mouse Model

P2Y14 Receptor Antagonists Reverse Chronic Neuropathic Pain in a Mouse Model

  • ACS Med Chem Lett. 2020 Apr 30;11(6):1281-1286. doi: 10.1021/acsmedchemlett.0c00115.
Fatma Mufti 1 Young-Hwan Jung 2 Luigino Antonio Giancotti 1 Jinha Yu 2 Zhoumou Chen 1 Ngan B Phung 2 Kenneth A Jacobson 2 Daniela Salvemini 1
Affiliations

Affiliations

  • 1 Department of Pharmacology and Physiology and the Henry and Amelia Nasrallah Center for Neuroscience, Saint Louis University School of Medicine, 1402 South Grand Boulevard, St. Louis, Missouri 63104, United States.
  • 2 Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-0810, United States.
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.

Figures