P2Y₁₄ Receptor Antagonists Reverse Chronic Neuropathic Pain in a Mouse Model

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.

P2Y14 Receptor as a Target for Neutrophilia Attenuation in Severe COVID-19 Cases: From Hematopoietic Stem Cell Recruitment and Chemotaxis to Thrombo‐inflammation

“…There are currently no clinical trials for the P2Y14R antagonist PPTN, although preclinical studies in rodent animal models displayed a safe use of PPTN, in both healthy mice and CF-like lung disease mice model [ 45 ]. Recently, new P2Y14R antagonists were synthesized and successfully tested in a mouse model of chronic pain [ 91 ], indicating that there are alternatives to PPTN for therapeutic applications. Our hypothesis is that the P2Y14R antagonist at low doses would allow neutrophil activation for SARS-CoV-2 removal, while preventing uncontrolled activation and lung infiltration by these cells.…”

Mechanisms of ATP release in pain: role of pannexin and connexin channels

“…Increased expression of both P2Y6 and P2Y11 has been observed following spinal nerve ligation, and pharmacologically blocking these receptors in the spinal cord was antiallodynic [ 32 ]. Novel antagonists of P2Y14 receptors were reported to ameliorate neuropathic pain in rats subjected to sciatic nerve injury; however, additional studies are required to support this finding [ 33 ]. Upregulation of P2Y12 receptor mRNA and protein in activated spinal microglia has been observed in different rodent models of nerve injury and both pharmacological inhibition and genetic deletion of P2Y12 receptors reduced tactile allodynia following nerve injury [ 34 , 35 ].…”

Adipocyte P2Y14 receptors play a key role in regulating whole-body glucose and lipid homeostasis

“…Taken together, these studies suggest that the development of dual antagonist(s) for these receptors or combination therapy with antagonists of both receptors may prove useful in treatment of obesity and T2D. P2Y 14 R antagonists have been under development for pulmonary diseases and acute kidney injury (44), as well as -potentially -pain and other inflammatory conditions (45). Known antagonists have demonstrated favorable preclinical safety.…”

“…P2Y 14 R antagonists have been under development for pulmonary diseases and acute kidney injury ( 44 ), as well as — potentially — pain and other inflammatory conditions ( 45 ). Known antagonists have demonstrated favorable preclinical safety.…”