TY - JOUR
T1 - P2Y14Receptor Antagonists Reverse Chronic Neuropathic Pain in a Mouse Model
AU - Mufti, Fatma
AU - Jung, Young Hwan
AU - Giancotti, Luigino Antonio
AU - Yu, Jinha
AU - Chen, Zhoumou
AU - Phung, Ngan B.
AU - Jacobson, Kenneth A.
AU - Salvemini, Daniela
N1 - Publisher Copyright:
Copyright © 2020 American Chemical Society.
PY - 2020/6/11
Y1 - 2020/6/11
N2 - 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.
AB - 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.
KW - G-protein-coupled receptor
KW - P2Y receptor
KW - antagonist
KW - chronic neuropathic pain
KW - mouse
UR - http://www.scopus.com/inward/record.url?scp=85088401079&partnerID=8YFLogxK
U2 - 10.1021/acsmedchemlett.0c00115
DO - 10.1021/acsmedchemlett.0c00115
M3 - Article
AN - SCOPUS:85088401079
SN - 1948-5875
VL - 11
SP - 1281
EP - 1286
JO - ACS Medicinal Chemistry Letters
JF - ACS Medicinal Chemistry Letters
IS - 6
ER -