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Selective novel inverse agonists for human GPR43 augment GLP-1 secretion

Selective novel inverse agonists for human GPR43 augment GLP-1 secretion
Park, Bi-OhKim, Seong HeonKong, Gye YeongKim, Da HuiKwon, Mi SoLee, Su UiKim, Mun-OckCho, SungchanLee, SangkuLee, Hyun-JunHan, Sang-BaeKwak, Young ShinLee, Sung BaeKim, Sunhong
DGIST Authors
Lee, Sung Bae
Issue Date
European Journal of Pharmacology, 771, 1-9
Article Type
Agents Interacting With Transmitter, Hormone or Drug ReceptorsBTI-A-202BTI-A-292BTI-A-404Calcium IonCompetitive InhibitionControlled StudyCyclic AMPCytoplasmDrug IdentificationDrug PotencyDrug ScreeningDrug SelectivityDrug StructureG Protein-Coupled ReceptorGLP-1Glucagon Like Peptide 1GPR43High Throughput ScreeningImmunoglobulin Enhancer Binding ProteinInverse AgonistMitogen-Activated Protein KinaseMitogen-Activated Protein Kinase P38Priority JournalProtein GPR43Protein SecretionSCFASignal TransductionStructure Activity RelationUnclassified Drug
GPR43/Free Fatty Acid Receptor 2 (FFAR2) is known to be activated by short-chain fatty acids and be coupled to Gi and Gq family of heterotrimeric G proteins. GPR43 is mainly expressed in neutrophils, adipocytes and enteroendocrine cells, implicated to be involved in inflammation, obesity and type 2 diabetes. However, several groups have reported the contradictory data about the physiological functions of GPR43, so that its roles in vivo remain unclear. Here, we demonstrate that a novel compound of pyrimidinecarboxamide class named as BTI-A-404 is a selective and potent competitive inverse agonist of human GPR43, but not the murine ortholog. Through structure-activity relationship (SAR), we also found active compound named as BTI-A-292. These regulators increased the cyclic AMP level and reduced acetate-induced cytoplasmic Ca2+ level. Furthermore, we show that they modulated the downstream signaling pathways of GPR43, such as ERK, p38 MAPK, and NF-κB. It was surprising that two compounds augmented the secretion of glucagon-like peptide 1 (GLP-1) in NCI-H716 cell line. Collectively, these novel and specific competitive inhibitors regulate all aspects of GPR43 signaling and the results underscore the therapeutic potential of them. © 2015 Elsevier B.V. All rights reserved.
Elsevier B.V.
Related Researcher
  • Author Lee, Sung-Bae SB LAB(Lab of Neurodegenerative diseases and Aging)
  • Research Interests Cellular mechanism of neurodegenerative diseases; Neuronal maintenance and remodeling; 퇴행성 뇌질환의 세포기전; 신경계 유지 및 리모델링 연구
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Department of Brain and Cognitive SciencesSB LAB(Lab of Neurodegenerative diseases and Aging)1. Journal Articles

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