RRC ID 41314
著者 Yamaura K, Kiyonaka S, Numata T, Inoue R, Hamachi I.
タイトル Discovery of allosteric modulators for GABAA receptors by ligand-directed chemistry.
ジャーナル Nat Chem Biol
Abstract The fast inhibitory actions of γ-aminobutyric acid (GABA) are mainly mediated by GABAA receptors (GABAARs) in the brain. The existence of multiple ligand-binding sites and a lack of structural information have hampered the efficient screening of drugs capable of acting on GABAARs. We have developed semisynthetic fluorescent biosensors for orthosteric and allosteric GABAAR ligands on live cells via coupling of affinity-based chemical labeling reagents to a bimolecular fluorescence quenching and recovery system. These biosensors were amenable to the high-throughput screening of a chemical library, leading to the discovery of new small molecules capable of interacting with GABAARs. Electrophysiological measurements revealed that one hit, 4,4',4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT), was a novel negative allosteric modulator capable of strongly suppressing GABA-induced chloride currents. Thus, these semisynthetic biosensors represent versatile platforms for screening drugs to treat GABAAR-related neurological disorders, and this strategy can be extended to structurally complicated membrane proteins.
巻・号 12(10)
ページ 822-30
公開日 2016-10-1
DOI 10.1038/nchembio.2150
PII nchembio.2150
PMID 27526031
MeSH Allosteric Regulation / drug effects Biosensing Techniques Dose-Response Relationship, Drug HEK293 Cells High-Throughput Screening Assays Humans Ligands Molecular Structure Phenols / chemistry Phenols / pharmacology* Pyrazoles / chemistry Pyrazoles / pharmacology* Receptors, GABA-A / metabolism* Small Molecule Libraries / chemistry Small Molecule Libraries / pharmacology* Structure-Activity Relationship
IF 12.587
引用数 19
WOS 分野 BIOCHEMISTRY & MOLECULAR BIOLOGY
リソース情報
遺伝子材料 pCAGGS (RDB08938)
ヒト・動物細胞 293T(RCB2202)