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P2Y14 Receptor Antagonists Reverse Chronic Neuropathic Pain in a Mouse Model
- Source :
- ACS Medicinal Chemistry Letters. 11:1281-1286
- Publication Year :
- 2020
- Publisher :
- American Chemical Society (ACS), 2020.
-
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.
- Subjects :
- P2Y receptor
010405 organic chemistry
Chemistry
Ligand binding assay
Organic Chemistry
Chronic pain
Antagonist
Pharmacology
medicine.disease
01 natural sciences
Biochemistry
0104 chemical sciences
010404 medicinal & biomolecular chemistry
Pharmacokinetics
In vivo
Drug Discovery
Neuropathic pain
medicine
Receptor
Subjects
Details
- ISSN :
- 19485875
- Volume :
- 11
- Database :
- OpenAIRE
- Journal :
- ACS Medicinal Chemistry Letters
- Accession number :
- edsair.doi...........5294955a197573842d2dc091376c94e0