Description
GW9508 (885101-89-3) is a selective agonist at the free fatty acid receptor, FFA1/4, (GPR40 and GPR120).1 Displays anti-allodynic and anti-hyperalgesic effects in mouse inflammatory and neuropathic pain models.2 Inhibits LPA-induced proliferation of DU145 and PC-3 cells.3 Decreases hepatic lipid accumulation in a high fat diet steatosis mouse model.4 Promotes brown adipose tissue thermogenesis.5
Uses
GW9508 is a GPR40 full agonist, used to regulate glucose in rats. Can be applied to the treatment of diabetes type 2. GPR120 selective and potent agonist also used in the treatment of diabetes type 2 due to GPR120’s ability to mediate GLP-1 secretion, insulin sensitization and anti-obesity effects.
Uses
GW9508, a selective FFA1/GPR40 agonist, may be used to differentiate and characterize the free fatty acid receptor FFA1/GPR40. GW9508 is used to study the role of FFA1/GPR40 receptors in processes such as the free fatty acid enhancement of glucose-stimulated insulin release and type 2 diabetes. GW9508 is used to study the process by which FFA1/GPR40 receptors protect from ovariectomy-induced bone loss in vivo though inhibition of osteoclast differentiation and suppress complete Freund′s adjuvant (CFA)-Induced inflammatory chronic pain.
Definition
ChEBI: 3-[4-[(3-phenoxyphenyl)methylamino]phenyl]propanoic acid is an aromatic amine.
Biological Activity
Potent and selective agonist for the free fatty acid receptor FFA 1 (GPR40) (pEC 50 values are 7.32, < 4.3 and < 4.3 for FFA 1 , FFA 2 and FFA 3 receptors respectively). Inactive against a range of other GPCRs, kinases, proteases, integrins and PPARs. Potentiates glucose-stimulated insulin secretion in MIN6 cells (pEC 50 = 6.14).
Biochem/physiol Actions
GW9508 is a selective FFA1/GPR40 agonist. GPR40 was formerly an orphan G protein-coupled receptor whose endogenous ligands have now been identified as free fatty acids (FFAs). The receptor, named FFA receptor 1, has been implicated in the pathophysiology of type 2 diabetes and is a drug target because of its role in FFA-mediated enhancement of glucose-stimulated insulin release. GW9508 showed greater than 500-fold selectivity for GPR40 over GPR41 and GPR43 and possessed a good in vitro and in vivo profile with excellent bioavailability. GW9508 stimulated intracellular Ca2+ mobilization in human embryonic kidney HEK-293 cells expressing GPR40 or GPR120, but not in the parent HEK-293 cell line. GW9508 dose dependently potentiated glucose-stimulated insulin secretion in MIN6 cells, but not in primary rat or mouse islets. GW9508 potentiates the KCl-mediated increase in insulin secretion in MIN6 cells.
References
1) Briscoe et al. (2006) Pharmacological regulation of insulin secretion in MIN6 cells through the fatty acid receptor GPR40: identification of agonist and antagonist molecules, Br. J. Pharmacol. 148 619
2) Karki et al. (2015), Attenuation of inflammatory and neuropathic pain behaviors in mice through activation of free fatty acid receptor GPR40; Mol. Pain, 11 6
3) Liu et al. (2015), Omega-3 fatty acids and other FFA4 agonists inhibit growth factor signaling in human prostate cancer cells; J. Pharmacol. Exp. Ther., 352 380
4) Ou et al. (2014), Activation of free fatty acid receptor 1 improves hepatic steatosis through a p38-dependent pathway; J. Mol. Endocrinol., 53 165
5) Kim et al. (2016), Eicosapentaenoic Acid Potentiates Brown Thermogenesis through FFAR4-dependent Up-regulation of miR-30b and miR-378; J. Biol. Chem., 291 2055
