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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
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Article Type
ACTIVATIONAgents Interacting With Transmitter, Hormone or Drug ReceptorsArticleBETA-ARRESTINSBTI-A-202BTI-A-404Bti A 292Bti A 404Calcium IonCHAIN FATTY-ACIDSCompetitive InhibitionControlled StudyCyclic AmpCytoplasmDrug IdentificationDrug PotencyDrug ScreeningDrug SelectivityDrug StructureENTEROENDOCRINE CELLSG Protein Coupled ReceptorGLP-1Glucagon Like Peptide 1GPR43GUT MICROBIOTAHigh Throughput ScreeningImmunoglobulin Enhancer Binding ProteinINFLAMMATORY RESPONSESInverse AgonistKAPPA-BMitogen Activated Protein KinaseMitogen Activated Protein Kinase P38PEPTIDE-1 SECRETIONPriority JournalPROTEIN-COUPLED RECEPTORSProtein GPR43Protein SecretionSCFASignal TransductionSPECIES ORTHOLOGSStructure 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.
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  • 이성배 Lee, Sung Bae 뇌과학과
  • 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 Sciences Laboratory of Neurodegenerative Diseases and Aging 1. Journal Articles


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