AH 7614 is a selective free fatty acid receptor 4 (FFA4/GPR120) antagonist. AH 7614 exhibits pIC50 values of 7.1, 8.1, and 8.1 for human, mouse, and rat FFA4, respectively. AH7 614 blocks linoleic acid and synthetic FFA4 agonist-induced intracellular Ca2+ response, β-arrestin recruitment, and receptor internalization to inhibit long-chain fatty acid signaling. AH 7614 regulates inflammation and metabolic responses by intervening in pathways such as TAK1/NF-κB. AH 7614 can be used in studies on obesity/type 2 diabetes, inflammatory diseases, and tumor chemosensitization[1-4].
In vitro, 1μM AH 7614 and 50μM GW9508 were used to treat oxidized low-density lipoprotein-induced HAEC cells for 24 hours. AH 7614 blocked the inhibitory effects of GW9508 on cytotoxicity, increased SA-β-Gal activity, ROS production, G0/G1 phase cell cycle arrest, and elevated expression of p53 and PAI-1[5]. 1μM AH 7614 was applied to PMA-induced Raw264.7 macrophages for 1 hour. AH 7614 increased PMA-induced ROS production[6]. AH 7614 and GW9508 were used to treat MCF-7 and T47-D cells for 48 hours. AH 7614 reversed GW9508-induced resistance of cells to epirubicin[7].
In vivo, 100μg/day AH 7614 was subcutaneously injected into the cranial vault of mice for 5 consecutive days. AH 7614 promoted the inhibitory effects on osteoclast formation and bone resorption, and increased TNF-α and RANKL mRNA expression[8]. Busulfan-induced mice received intraperitoneal injections of AH 7614 (100μg; once every two days) for 12 consecutive weeks. AH 7614 caused disordered seminiferous tubules, reduced seminiferous tubule epithelial thickness, decreased sperm count and motility, reduced MVH+ germ cells, Lin28+ undifferentiated spermatogonia, and c-kit+ differentiated spermatogonia, and inhibited BMP4, PLZF, Lin28, c-kit, Stra8, and SYCP3 protein expression[9]. Carrageenan-induced Holtzman rats received a single plantar injection of 99nmol AH 7614 into the hind paw. Resolvin E1 was injected 15 minutes later. AH 7614 did not affect carrageenan-induced hind paw edema and mechanical pain threshold changes[10].
References:[1] Moghaddam F, Binwal M, Green AJ, et al. Agonism of FFA4/GPR120 activates tyrosine hydroxylase and confers neuroprotection from 6-OHDA-induced cytotoxicity in PC12 cells and in a rat 6-OHDA model of Parkinson's disease. Biochem Pharmacol. 2026 Mar;245:117685.
[2] Watterson KR, Hansen SVF, Hudson BD, et al. Probe-Dependent Negative Allosteric Modulators of the Long-Chain Free Fatty Acid Receptor FFA4. Mol Pharmacol. 2017 Jun;91(6):630-641.
[3] Wang J, Cai L, Liu J, et al. Fish oil reduces intestinal fat absorption by promoting lacteal junction zippering via GPR120-VEGFR3-MLCK pathway. J Adv Res. 2026 Feb;80:423-433.
[4] Chen W-T, Chen S-Y, Wu D-W, et al. Effect of icosapent ethyl on susceptibility to ventricular arrhythmias in postinfarcted rat hearts: Role of GPR120-mediated connexin43 phosphorylation. J Cell Mol Med. 2020;24:9267-9279.
[5] Liu R, Cheng F, Zeng K, et al. GPR120 Agonist GW9508 Ameliorated Cellular Senescence Induced by ox-LDL. ACS Omega. 2020 Dec 8;5(49):32195-32202.
[6] Cheshmehkani A, Senatorov IS, Dhuguru J, et al. Free-fatty acid receptor-4(FFA4) modulates ROS generation and COX-2 expression via the C-terminal β-arrestin phosphosensor in Raw 264.7 macrophages. Biochem Pharmacol. 2017 Dec 15;146:139-150.
[7] Wang X, He S, Gu Y, et al. Fatty acid receptor GPR120 promotes breast cancer chemoresistance by upregulating ABC transporters expression and fatty acid synthesis. EBioMedicine. 2019 Feb;40:251-262.
[8] Kishikawa A, Kitaura H, Kimura K, et al. Docosahexaenoic Acid Inhibits Inflammation-Induced Osteoclast Formation and Bone Resorption in vivo Through GPR120 by Inhibiting TNF-α Production in Macrophages and Directly Inhibiting Osteoclast Formation. Front Endocrinol (Lausanne). 2019 Mar 15;10:157.
[9] Jing J, Ouyang L, Zhang H, et al. Omega-3 polyunsaturated fatty acids and its metabolite 12-HEPE rescue busulfan disrupted spermatogenesis via target to GPR120. Cell Prolif. 2024;57(2):e13551.
[10] Fonseca FCS, Orlando RM, Turchetti-Maia RMM, et al. Comparative effects of the w3 polyunsaturated fatty acid derivatives resolvins E1 and D1 and protectin DX in models of inflammation and pain. J Inflamm Res. 2017;10:119-133.