Free fatty acid receptor 1 (FFA1), also known as GPR40, is a class of G protein-coupled receptors. FFA1 strongly expresses in pancreatic cells, but less in the brain. Meanwhile, FFA1 combines with free fatty acids and acts as a nutritional sensor to regulate energy homeostasis. Medium to long-chain fatty acids activates FFA1 protein. Particularly, the FFA1 receptor expresses in the brain and monocytes, especially in the pancreas, especially in beta cells. Obviously, GPR40 is coupled with G α Q class G proteins, resulting in inositol phosphate formation and increased intracellular calcium. Nonetheless, the increase of intracellular calcium-mediated by GPR40 is Glucose-dependent. Stimulation of GPR40 in pancreatic beta cells leads to the decrease of voltage-gated potassium channels in the protein kinase A-dependent pathway.

Various pathways increased the amount of GPR40. Importantly, GPR40 is related to the well-known mechanism of acute stimulation of insulin and glucagon secretion by fatty acids. Targeting GPR40 with synthetic agonists may represent a new approach to the treatment of type 2 diabetes. Today, let’s study an orally bioavailable and partial agonist of GPR40/FFA1, AMG 837.

AMG 837 is an Orally Active and Partial Agonist of GPR40/FFA1.

First of all, AMG 837 inhibits specific [³H]AMG 837 binding at the human FFA1 receptor with a pIC₅₀ of 8.13. Besides, AMG 837 can enhance insulin secretion and lower glucose levels in rodents.

In the second place, AMG 837 with 1 nM-10 μM stimulates insulin secretion in a glucose-dependent manner with an EC₅₀ of 142 nM on islets isolated from mice. Moreover, AMG 837 stimulates Ca²⁺ flux with the EC₅₀s of 13.5, 22.6 and 31.7 nM for human, mouse and rat receptors in CHO cells, respectively.

Last but not the least, AMG 837 with 0.03-0.3 mg/kg by a single p.o. improves glucose tolerance and enhances insulin secretion in Sprague-Dawley rats. Furthermore, AMG 837 reduces glucose levels and increases insulin levels following glucose challenge in vivo. Additionally, AMG 837 displays excellent oral bioavailability (F = 84%) and a total plasma C_max of 1.4 µM.

All in all, AMG 837 is a potent, orally bioavailable and partial agonist of GPR40/FFA1.

References:

Daniel CHL, et, al. PLoS One. 2011; 6(11): e27270.