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  • Compounds and were tested for pharmacodynamic effects in a


    Compounds , and were tested for pharmacodynamic effects in a mouse oral glucose tolerance test (oGTT) in wild-type and GPR120 deficient mice, and each compound demonstrated GPR120 mechanism-based effects. Data for compound is shown in , indicating mechanism-based reduction in glucose excursion at both 30 and 100mpk PO doses. In summary, an ultra high-throughput screen provided hit with moderate GPR120 potency, which was ultimately progressed into a novel, potent and selective benzofuran propanoic rosmarinic acid series. These compounds demonstrated acute mechanism-based effects in mouse oGTT. Further modification of the benzofuran core leading to the discovery of additional novel series will be the subject of future manuscripts.
    Introduction Of the GPCRs under investigation for their potential as drug targets, GPR120 [also known as free fatty acid receptor (FFA)4] is among those that have been progressed as a potential targeted receptor for the alleviation of metabolic diseases. GPR120 has been identified as a member of a family of free fatty acid receptors including GPR40 (also known as FFA1), GPR41 (FFA3) and GPR43 (FFA2), which have been reviewed extensively elsewhere 1, 2, 3, 4. As the name suggests, this family of receptors are activated by free FAs of varying chain length with GPR41 and GPR43 being activated predominantly by short-chain FAs, whereas GPR40 and GPR120 are activated by long-chain FAs (LCFAs) [4]. As a result of this, efforts to understand the explicit functions of these receptors in isolation have been clouded by nonspecific endogenous and synthetic ligands for GPR40 and GPR120. Ongoing works have been able to develop more selective chemical agonists and antagonists at these receptors, which has enhanced the current understanding of the roles of these receptors. But caution is still needed in many instances in attributing changes in function solely to one of these receptors. When looking at GPR120 specifically, this receptor has been implicated in a number of processes including release of gastrointestinal peptides, inflammation, adipogenesis, lipogenesis, glucose intolerance, insulin sensitivity and food preference 5, 6, 7, 8, 9, 10. These factors interrelate to influence systemic metabolic function in physiological and pathophysiological conditions. Herein, we discuss the recent advances in research regarding the roles of GPR120 and how pharmaceutical agents at this receptor could be used in the prevention and treatment of metabolic diseases.
    GPR120 GPR120 was first identified as an orphan GPCR by Fredriksson et al.[11], who determined the chromosomal location for human GPR120 to be 10q23.33. Human GPR120 was subsequently shown to exist as two splice variants, a short (361 amino acids; accession numbers: RNA – GenBank ID: BC101175 and Protein – GenBank ID: AAI01176.1) and a long (377 amino acid; accession numbers: RNA – NCBI Reference Sequence ID: NM_181745 and Protein – NCBI Reference Sequence ID: NP_859529.2) isoform 6, 10, 12, 13 (Fig. 1). The predicted molecular weight of the long isoform is 42kDa [11]. Of particular interest, the long GPR120 isoform appears to be human specific, being undetectable in the cynomolgus monkey [14]. Mouse GPR120 appears to correlate more closely with the short isoform present in humans having 361 amino acid residues [11].
    Tissue distribution of GPR120 GPR120 is widely expressed in a number of tissue types, and is most abundantly expressed in lung and colonic tissues [6]. This diverse localization of GPR120 is likely related to the broad spectrum of effects GPR120 elicits with expression also being reported in tissues involved in homeostatic regulation of metabolic health and inflammatory and/or immune processes, including the brain, thymus, pituitary, small intestine, white adipose tissues, taste buds, skeletal muscle, heart and liver 6, 7, 10, 15. However, it appears that species differences exist between the distribution and density of GPR120 (Table 1). As can also be seen in Table 1, GPR120 demonstrates a divergence in tissue localization between different species so that care should be taken when extrapolating results from animal models to a potential therapeutic application in humans because the interspecies differences in expression can confound these findings. It should also be noted, however, that differences in the relative sensitivity of detection techniques used can in part account for some of the variability of expression. Moreover, studies show selective tissue-specific upregulation of GPR120 expression in the extensor digitorum longus (EDL) skeletal muscle, heart and adipose tissues following high fat feeding leading to obesity 5, 7, 15. Interestingly Wu et al.[16] demonstrated that not only is GPR120 expressed in a panel of colorectal cancer cell lines and biopsies of human colorectal cancers but this receptor is significantly induced by malignancy in colorectal cancer patients.