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Papers: 20 Jun 2020 - 26 Jun 2020

Animal Studies, Pharmacology/Drug Development

2020 Jun 11

ACS Med Chem Lett



P2Y Receptor Antagonists Reverse Chronic Neuropathic Pain in a Mouse Model.


Mufti F, Jung Y-H, Giancotti L A, Yu J, Chen Z, Phung NB, Jacobson KA, Salvemini D
ACS Med Chem Lett. 2020 Jun 11; 11(6):1281-1286.
PMID: 32551012.


Eight P2YR 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). P2YR 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 and -acetyl analogue , 10 μmol/kg, i.p.) achieved complete pain reversal (100%) at 1 to 2 h, with relief evident up to 5 h for (41%). A reversed triazole analogue reached 87% maximal protection. Receptor affinity was determined using a fluorescent antagonist binding assay, indicating similar mouse and human P2YR affinity. The mP2YR affinity was only partially predictive of efficacy, suggesting the influence of pharmacokinetic factors. Thus P2YR is a potential therapeutic target for treating chronic pain.