Discovery of potent GPR120 activators with fatty orosensation enhancement activity.

GPR120 is expressed in the tongue and plays an important role in fatty acid taste perception. Natural polyunsaturated fatty acids, including α-linolenic acid and linoleic acid, are found in various edible oils such as soybean, rapeseed, and safflower oils. These fatty acids activate GPR120 but are susceptible to oxidation during storage and heating. To address these limitations while retaining GPR120 activity, a series of conformationally restricted, aliphatic side-chain-conjugated aryl short-chain fatty acid derivatives was synthesized. Several compounds exhibited potent GPR120-mediated activity. Compound 20, one of the most active compounds, enhanced fatty orosensation in a preliminary sensory evaluation.