Molecular Pharmacology Group, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom (B.D.H., A.E.M., J.D.P., H.H., G.M.); Department of Physics, Chemistry, and Pharmacy, University of Southern Denmark, Odense, Denmark (B.S., E.C., T.U.); and MRC Toxicology Unit, University of Leicester, Leicester, United Kingdom (A.J.B., A.B.T.).
Mol Pharmacol. 2013 Nov;84(5):710-25. doi: 10.1124/mol.113.087783. Epub 2013 Aug 26.
TUG-891 [3-(4-((4-fluoro-4'-methyl-[1,1'-biphenyl]-2-yl)methoxy)phenyl)propanoic acid] was recently described as a potent and selective agonist for the long chain free fatty acid (LCFA) receptor 4 (FFA4; previously G protein-coupled receptor 120, or GPR120). Herein, we have used TUG-891 to further define the function of FFA4 and used this compound in proof of principle studies to indicate the therapeutic potential of this receptor. TUG-891 displayed similar signaling properties to the LCFA α-linolenic acid at human FFA4 across various assay end points, including stimulation of Ca²⁺ mobilization, β-arrestin-1 and β-arrestin-2 recruitment, and extracellular signal-regulated kinase phosphorylation. Activation of human FFA4 by TUG-891 also resulted in rapid phosphorylation and internalization of the receptor. While these latter events were associated with desensitization of the FFA4 signaling response, removal of TUG-891 allowed both rapid recycling of FFA4 back to the cell surface and resensitization of the FFA4 Ca²⁺ signaling response. TUG-891 was also a potent agonist of mouse FFA4, but it showed only limited selectivity over mouse FFA1, complicating its use in vivo in this species. Pharmacologic dissection of responses to TUG-891 in model murine cell systems indicated that activation of FFA4 was able to mimic many potentially beneficial therapeutic properties previously reported for LCFAs, including stimulating glucagon-like peptide-1 secretion from enteroendocrine cells, enhancing glucose uptake in 3T3-L1 adipocytes, and inhibiting release of proinflammatory mediators from RAW264.7 macrophages, which suggests promise for FFA4 as a therapeutic target for type 2 diabetes and obesity. Together, these results demonstrate both potential but also significant challenges that still need to be overcome to therapeutically target FFA4.
TUG-891（3-（4-（（4-氟-4'-甲基-[1,1'-联苯]-2-基）甲氧基）苯基）丙基）酸）最近被描述为一种有效的、选择性的长链游离脂肪酸（LCFA）受体 4（FFA4；以前称为 G 蛋白偶联受体 120，或 GPR120）激动剂。在此，我们使用 TUG-891 进一步定义了 FFA4 的功能，并使用该化合物进行了原理验证研究，以表明该受体的治疗潜力。TUG-891 在各种测定终点（包括刺激 Ca²⁺动员、β-arrestin-1 和 β-arrestin-2 募集以及细胞外信号调节激酶磷酸化）中显示出与 LCFA α-亚麻酸在人 FFA4 上相似的信号转导特性。TUG-891 激活人 FFA4 也导致受体的快速磷酸化和内化。虽然这些后续事件与 FFA4 信号反应的脱敏有关，但 TUG-891 的去除允许 FFA4 迅速回收至细胞表面并重新敏化 FFA4 Ca²⁺信号反应。TUG-891 也是小鼠 FFA4 的有效激动剂，但它对小鼠 FFA1 的选择性有限，这使得它在该物种体内的应用变得复杂。在模型鼠细胞系统中对 TUG-891 反应的药理学剖析表明，FFA4 的激活能够模拟以前报道的许多潜在有益的治疗特性，包括刺激肠内分泌细胞分泌胰高血糖素样肽-1、增强 3T3-L1 脂肪细胞中的葡萄糖摄取以及抑制 RAW264.7 巨噬细胞中促炎介质的释放，这表明 FFA4 作为 2 型糖尿病和肥胖症的治疗靶点具有潜力。综上所述，这些结果既展示了 TUG-891 的潜在应用，也展示了仍需克服的重大挑战，以实现 FFA4 的治疗靶向。
