YM 58483 is a pyrazole-derived inhibitor of CRAC channels that inhibits Ca2+ signals with an IC50 value of 100nM [1]. YM 58483 suppresses the CRAC, TRPC3, and TRPC5 channels and facilitates the TRPM4 channel, reducing cytokine production and NFAT dephosphorylation [2]. YM 58483 has been widely used as a potent analgesic to alleviate thermal hyperalgesia and mechanical hyperalgesia in mice[3].
In vitro, YM 58483 treatment for 48 hours significantly inhibited the production of IL-5 and IL-13 in human peripheral blood cells induced by phytohemagglutinin-P (PHA), with IC50 values of 125nM and 148nM, respectively[4]. The pretreatment of YM 58483 for 1 hour inhibited the production of IL-4 and IL-5 in conalbumin-stimulated D10.G4.1 cells, with IC50 values of 200nM and 180nM, respectively[5]. Treatment with 30µM YM 58483 for 24 hours significantly reduced the proliferation of glioblastoma stem cells (GSC) and decreased the expression of SOX2[6].
In vivo, YM 58483 treatment via oral administration at a dose of 30mg/kg/day for 10 consecutive days significantly inhibited the activity of donor anti-host cytotoxic T lymphocytes (CTL) and the production of IFN-γ, and reduced the number of donor T cells in the spleen within the mouse model of graft-versus-host disease (GVHD)[7]. Oral administration of 10mg/kg dose of YM 58483 daily for 10 consecutive days significantly inhibited the development of collagen-induced paw edema in mice, alleviated joint damage in mice, and improved spontaneous movement defects[8].
References:
[1] Parekh A B. Store-operated CRAC channels: function in health and disease[J]. Nature reviews Drug discovery, 2010, 9(5): 399-410.
[2] Rubaiy H N. ORAI calcium channels: regulation, function, pharmacology, and therapeutic targets[J]. Pharmaceuticals, 2023, 16(2): 162.
[3] Gao R, Gao X, Xia J, et al. Potent analgesic effects of a store-operated calcium channel inhibitor[J]. PAIN®, 2013, 154(10): 2034-2044.
[4] Ohga K, Takezawa R, Yoshino T, et al. The suppressive effects of YM-58483/BTP-2, a store-operated Ca2+ entry blocker, on inflammatory mediator release in vitro and airway responses in vivo[J]. Pulmonary pharmacology & therapeutics, 2008, 21(2): 360-369.
[5] Yoshino T, Ishikawa J, Ohga K, et al. YM-58483, a selective CRAC channel inhibitor, prevents antigen-induced airway eosinophilia and late phase asthmatic responses via Th2 cytokine inhibition in animal models[J]. European journal of pharmacology, 2007, 560(2-3): 225-233.
[6] Terrié E, Déliot N, Benzidane Y, et al. Store-operated calcium channels control proliferation and self-renewal of cancer stem cells from glioblastoma[J]. Cancers, 2021, 13(14): 3428.
[7] Ohga K, Takezawa R, Arakida Y, et al. Characterization of YM-58483/BTP2, a novel store-operated Ca2+ entry blocker, on T cell-mediated immune responses in vivo[J]. International immunopharmacology, 2008, 8(13-14): 1787-1792.
[8] Gao X H, Gao R, Tian Y Z, et al. A store‐operated calcium channel inhibitor attenuates collagen‐induced arthritis[J]. British journal of pharmacology, 2015, 172(12): 2991-3002.
YM 58483是一种吡唑衍生的CRAC通道抑制剂，能抑制Ca2+信号，IC50值为100nM[1]。YM 58483可抑制CRAC、TRPC3和TRPC5通道，并促进TRPM4通道，从而减少细胞因子的产生和NFAT的去磷酸化[2]。YM 58483已被广泛用作一种强效镇痛剂，以减轻小鼠的热痛觉过敏和机械性痛觉过敏[3]。
在体外，YM 58483处理人外周血细胞48小时，显著抑制了植物phytohemagglutinin-P(PHA)诱导的IL-5和IL-13的产生，IC50值分别为125nM和148nM[4]。YM 58483预处理1小时可抑制conalbumin刺激的D10.G4.1细胞中IL-4和IL-5的产生，IC50值分别为200nM和180nM[5]。30µM的YM 58483处理胶质母细胞瘤干细胞(GSC)24小时，显著降低了细胞增殖和SOX2的表达[6]。
在体内，在移植物抗宿主病小鼠模型(GVHD)中，连续10天口服30mg/kg/day剂量的YM 58483，显著抑制了供体抗宿主细胞毒性T淋巴细胞(CTL)的活性和IFN-γ的产生，并减少了脾脏中供体T细胞的数量[7]。连续10天每日口服10mg/kg剂量的YM 58483，显著抑制了胶原诱导的小鼠爪水肿的发展，减轻了小鼠的关节损伤，并改善了自发性运动缺陷[8]。