A-317491 is a high-affinity and selective antagonist of P2X3 and P2X2/3 receptor activation, with Ki values of 22 and 92nM for rat P2X3 and P2X2/3, respectively [1]. A-317491 acts in the gp120 protein to inhibit the gp120-initiated P2X3 activation, decrease the sensitizing dorsal root ganglia (DRG) primary afferents, and reduce the signal transmission of neuropathic pain in gp120-treated rats[2]. A-317491 can be used to relieve the mechanical and thermal hyperalgesia of endometriotic rats [3].
In vitro, A-317491 (100µM) treatment of bovine chondrocytes for 24 hours reduced α,β-methyleneATP-induced NO production and decreased ATP-mediated PGE2 release in bovine chondrocytes[4].
In vivo, A-317491 treatment (30μmol/kg; s.c.; twice daily) for 10 days alleviated cancer-induced bone pain in NCTC clone 2472 cell-xenograft mouse models[5]. A single intrathecal injection of A-317491 (10μg dissolved in 20μl of normal saline) was administered over 3 days, which alleviated the overactive bladder evoked by 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)-induced colitis[6]. Intramuscular injections of A-317491 (60μg dissolved in normal saline) prevented the mechanical muscle hyperalgesia when administered 30 or 60min after the beginning of static contraction in rats[7].
References:
[1] Jarvis M F, Burgard E C, McGaraughty S, et al. A-317491, a novel potent and selective non-nucleotide antagonist of P2X3 and P2X2/3 receptors, reduces chronic inflammatory and neuropathic pain in the rat[J]. Proceedings of the national academy of sciences, 2002, 99(26): 17179-17184.
[2] Yi Z, Rao S, Ouyang S, et al. A317491 relieved HIV gp120-associated neuropathic pain involved in P2X3 receptor in dorsal root ganglia[J]. Brain Research Bulletin, 2017, 130: 81-89.
[3] Yuan M, Ding S, Meng T, et al. Effect of A-317491 delivered by glycolipid-like polymer micelles on endometriosis pain[J]. International Journal of Nanomedicine, 2017: 8171-8183.
[4] Varani K, De Mattei M, Vincenzi F, et al. Pharmacological characterization of P2X1 and P2X3 purinergic receptors in bovine chondrocytes[J]. Osteoarthritis and cartilage, 2008, 16(11): 1421-1429.
[5] Hansen R R, Nasser A, Falk S, et al. Chronic administration of the selective P2X3, P2X2/3 receptor antagonist, A-317491, transiently attenuates cancer-induced bone pain in mice[J]. European journal of pharmacology, 2012, 688(1-3): 27-34.
[6] Dong X Y, Yang Y, Luo S, et al. Upregulation of P2X3 receptors in primary afferent pathways involves in colon-to-bladder cross-sensitization in rats[J]. Frontiers in Physiology, 2022, 13: 920044.
[7] de Melo Aquino B, da Silva dos Santos D F, Jorge C O, et al. P2X3 receptors contribute to muscle pain induced by static contraction by a mechanism dependent on neutrophil migration[J]. Purinergic signalling, 2019, 15(2): 167-175.
A-317491是一种高亲和力、选择性的P2X3和P2X2/3受体激活拮抗剂，其对大鼠P2X3和P2X2/3的Ki值分别为22nM和92nM[1]。A-317491作用于gp120蛋白，抑制gp120启动的P2X3激活，减少gp120处理大鼠中背根神经节（DRG）初级传入神经的敏化，并降低神经病理性疼痛的信号传递[2]。A-317491可用于缓解子宫内膜异位症大鼠的机械性和热痛觉过敏[3]。
在体外，使用100µM的A-317491处理牛软骨细胞24小时，减少了α,β-methyleneATP诱导的一氧化氮生成，并降低了ATP介导的PGE2释放[4]。
在体内，每日两次皮下注射A-317491（30µmol/kg），持续10天，缓解了NCTC clone 2472细胞异种移植小鼠模型中癌症诱导的骨痛[5]。在3天内单次鞘内注射A-317491（10µg溶解于20µl生理盐水中），缓解了由2,4,6-三硝基苯磺酸（TNBS）诱导的结肠炎引发的膀胱过度活动[6]。在静态收缩开始后30或60分钟，肌肉注射A-317491（60µg溶解于生理盐水），可预防大鼠机械性肌肉痛觉过敏的发生[7]。