title: Novel selective ligands for free fatty acid receptors GPR120 and GPR40.
abstract: GPR120 and GPR40 are G-protein-coupled receptors whose endogenous ligands are medium- and long-chain free fatty acids, and they are thought to play an important physiological role in insulin release. Despite recent progress in understanding their roles, much still remains unclear about their pharmacology, and few specific ligands for GPR120 and GPR40 besides medium- to long-chain fatty acids have been reported so far. To identify new selective ligands for these receptors, more than 80 natural compounds were screened, together with a reference compound MEDICA16, which is known to activate GPR40, by monitoring the extracellular regulated kinase (ERK) and [Ca(2+)](i) responses in inducible and stable expression cell lines for GPR40 and GPR120, respectively. MEDICA16 selectively activated [Ca(2+)](i) response in GPR40-expressing cells but not in GPR120-expressing cells. Among the natural compounds tested, grifolin derivatives, grifolic acid and grifolic acid methyl ether, promoted ERK and [Ca(2+)](i) responses in GPR120-expressing cells, but not in GPR40-expressing cells, and inhibited the alpha-linolenic acid (LA)-induced ERK and [Ca(2+)](i) responses in GPR120-expressing cells. Interestingly, in accordance with the pharmacological profiles of these compounds, similar profiles of glucagon-like peptide-1 secretion were seen for mouse enteroendocrine cell line, STC-1 cells, which express GPR120 endogenously. Taken together, these studies identified a selective GPR40 agonist and several GPR120 partial agonists. These compounds would be useful probes to further investigate the physiological and pharmacological functions of GPR40 and GPR120.
authors.affiliation: Department of Genomic Drug Discovery Science, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-shimo-adachi-cho, Sakyo-ku, Kyoto, Japan. t-hara@fc.ritsumei.ac.jp
authors.forename: Takafumi
authors.initials: T
authors.lastname: Hara
authors.forename: Akira
authors.initials: A
authors.lastname: Hirasawa
authors.forename: Qi
authors.initials: Q
authors.lastname: Sun
authors.forename: Keiko
authors.initials: K
authors.lastname: Sadakane
authors.forename: Chisato
authors.initials: C
authors.lastname: Itsubo
authors.forename: Tomoyo
authors.initials: T
authors.lastname: Iga
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Adachi
authors.forename: Taka-aki
authors.initials: TA
authors.lastname: Koshimizu
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Hashimoto
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Asakawa
authors.forename: Gozoh
authors.initials: G
authors.lastname: Tsujimoto
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008024:Ligands; D051379:Mice; D010169:Palmitic Acids / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D013729:Terpenes / Q000737:chemistry / Q000494:pharmacology
chemical_list: C473034:FFAR1 protein, human; C519853:FFAR4 protein, human; D008024:Ligands; D010169:Palmitic Acids; D043562:Receptors, G-Protein-Coupled; D013729:Terpenes; C058858:grifolin; C056166:MEDICA 16; D048049:Extracellular Signal-Regulated MAP Kinases; D002118:Calcium