Development of Free Fatty Acid Receptor 4 (FFA4/GPR120) Agonists in Health Science

Abstract

Till the 21 st century, fatty acids were considered as merely building blocks for triglycerides, phospholipids, or cholesteryl esters. However, the discovery of G protein-coupled receptors (GPCRs) for free fatty acids at the beginning of the 21 st century challenged that idea and paved way for a new field of research, merged into the field of receptor pharmacology for intercellular lipid mediators. Among the GPCRs for free fatty acids, free fatty acid receptor 4 (FFA4, also known as GPR120) recognizes long-chain polyunsaturated fatty acids such as DHA and EPA. It is significant in drug discovery because it regulates obesity-induced metaflammation and GLP-1 secretion. Our study reviews information on newly developed FFA4 agonists and their application in pathophysiologic studies and drug discovery. It also offers a potency comparison of the FFA4 agonists in an AP-TGF-α shedding assay.

Anti-Atherosclerotic Potential of Free Fatty Acid Receptor 4 (FFAR4)

“…Long-and medium-chain fatty acids are derived mainly from dietary triglycerides, while short chain fatty acids are produced by gut bacteria in the process of fermentation of indigestible dietary fiber. In animals, fatty acids are also synthesized de novo from carbohydrates mainly in the liver, adipose tissue, and mammary glands [1][2][3]. In tissues, the FAs are present in esters: triglycerides, phospholipids, and cholesteryl esters, however in plasma they are present in a nonesterified, free form (free fatty acids, -FFAs).…”

“…Classically, FFAs have been considered the basic nutrients, but since the 1990s they have been increasingly recognized as signaling molecules by acting on various types of receptors and fatty acid binding proteins (FABPs). Next to the well-characterized intracellular receptors for FFAs such as PPARs [2,4], several types of G protein-coupled membrane receptors have been characterized in recent years [3,5].…”

“…The receptors activated by FAs include the family of FFARs of rhodopsin-like receptors: GPR40 (FFAR1), GPR41 (FFAR3), GPR43 (FFAR2), GPR120 (FFAR4), and several other, less characterized GPCRs (GPR84, GPR109A, GPR170, GPR31, GPR132, GPR119, and Olfr78 [1][2][3]5,11]. Major FFAR are activated by distinct classes of FA ligands: the SCFA bind to FFAR3 and FFAR2, the MCFA to FFAR1 and GPR84, and the LCFA to FFAR1 and FFAR4.…”

“…An overview of synthetic FFAR4 agonists has been recently published [3]. GW9508 (3-[4-({[3-(phenyloxy)phenyl]methyl}amino)phenyl] propanoic acid), was the first synthetic agonist for FFAR4 and FFAR1 [18].…”

“…It should be noted that several reports described a reduced selectivity of TUG-891 at mouse FFAR4, nevertheless it remains a valuable tool and a first choice option in the research related to physiology and signaling of FFAR4 [3]. Between 2014 and 2016, other compounds strongly accumulating FFAR4 appeared in basic research: compound A, Metabolex compounds (metabolex 36 and compound B), Astra Zeneca compounds (AZ-423, AZ-670), TUG-1197, and KDT501 [3]. AH-7614, described in 2014 by Sparks et al, is a negative allosteric modulator of FFAR4 [19].…”