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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, BO[Park, Bi-Oh]; Kim, SH[Kim, Seong Heon]; Kong, GY[Kong, Gye Yeong]; Kim, DH[Kim, Da Hui]; Kwon, MS[Kwon, Mi So]; Lee, SU[Lee, Su Ui]; Kim, MO[Kim, Mun-Ock]; Cho, S[Cho, Sungchan]; Lee, S[Lee, Sangku]; Lee, HJ[Lee, Hyun-Jun]; Han, SB[Han, Sang-Bae]; Kwak, YS[Kwak, Young Shin]; Lee, SB[Lee, Sung Bae]; Kim, S[Kim, Sunhong]
- DGIST Authors
- Lee, SB[Lee, Sung Bae]
- Issue Date
- European Journal of Pharmacology, 771, 1-9
- Article Type
- Agents Interacting With Transmitter, Hormone or Drug Receptors; BTI-A-202; BTI-A-292; BTI-A-404; Calcium Ion; Competitive Inhibition; Controlled Study; Cyclic AMP; Cytoplasm; Drug Identification; Drug Potency; Drug Screening; Drug Selectivity; Drug Structure; G Protein-Coupled Receptor; GLP-1; Glucagon Like Peptide 1; GPR43; High Throughput Screening; Immunoglobulin Enhancer Binding Protein; Inverse Agonist; Mitogen-Activated Protein Kinase; Mitogen-Activated Protein Kinase P38; Priority Journal; Protein GPR43; Protein Secretion; SCFA; Signal Transduction; Structure Activity Relation; Unclassified 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
Lee, Sung Bae
SB LAB(Lab of Neurodegenerative diseases and Aging)
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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