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Identification and in vitro pharmacological characterization of a novel and selective alpha 7 nicotinic acetylcholine receptor agonist, Br-IQ17B
Tang, Jing-shu1; Xie, Bing-xue2; Bian, Xi-ling3; Xue, Yu2; Wei, Ning-ning3; Zhou, Jing-heng3; Hao, Yu-chen3; Li, Gang1; Zhang, Liang-ren2; Wang, Ke-wei1,2,3,4
关键词alpha 7 nAChR Br-IQ17B electrophysiology ERK1/2 phosphorylation GABAergic synaptic transmission CNS diseases
刊名ACTA PHARMACOLOGICA SINICA
2015-07-01
DOI10.1038/aps.2015.9
36期:7页:800-812
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Chemistry, Multidisciplinary ; Pharmacology & Pharmacy
研究领域[WOS]Chemistry ; Pharmacology & Pharmacy
关键词[WOS]PROOF-OF-CONCEPT ; ALZHEIMERS-DISEASE ; SYNAPTIC-TRANSMISSION ; HIPPOCAMPAL-NEURONS ; NERVOUS-SYSTEM ; ACH RECEPTORS ; SH-SY5Y CELLS ; SCHIZOPHRENIA ; BRAIN ; RAT
英文摘要

Aim: Alpha7-nicotinic acetylcholine receptor (alpha 7 nAChR) is a ligand-gated Ca2+-permeable ion channel implicated in cognition and neuropsychiatric disorders. Activation of alpha 7 nAChR improves learning, memory, and sensory gating in animal models. To identify novel alpha 7 nAChR agonists, we synthesized a series of small molecules and characterized a representative compound, Br-IQ17B, N-[(3R)-1-azabicyclo[2,2,2]oct-3-yl]-5-bromoindolizine-2-carboxamide, which specifically activates alpha 7 nAChR.

Methods: Two-electrode voltage clamp (TEVC) recordings were primarily used for screening in Xenopus oocytes expressing human alpha 7 nAChR. Assays, including radioisotope ligand binding, Western blots, whole-cell recordings of hippocampal culture neurons, and spontaneous IPSC recordings of brain slices, were also utilized to evaluate and confirm the specific activation of alpha 7 nAChR by Br-IQ17B.

Results: Br-IQ17B potently activates alpha 7 nAChR with an EC50 of 1.8 +/- 0.2 mu mol/L. Br-IQ17B is selective over other subtypes such as alpha 4 beta 2 and alpha 3 beta 4, but it blocks 5-HT3A receptors. Br-IQ17B displaced binding of the alpha 7 blocker [H-3]-MLA to hippocampal crude membranes with a K-i of 14.9 +/- 3.2 nmol/L. In hippocampal neurons, Br-IQ17B evoked alpha 7-like currents that were inhibited by MLA and enhanced in the presence of the alpha 7 PAM PNU-120596. In brain slice recordings, Br-IQ17B enhanced GABAergic synaptic transmission in CA1 neurons. Mechanistically, Br-IQ17B increased ERK1/2 phosphorylation that was MLA-sensitive.

Conclusion: We identified the novel, potent, and selective alpha 7 agonist Br-IQ17B, which enhances synaptic transmission. Br-IQ17B may be a helpful tool to understand new aspects of alpha 7 nAChR function, and it also has potential for being developed as therapy for schizophrenia and cognitive deficits.

语种英语
WOS记录号WOS:000357477600004
引用统计
被引频次:3[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/62534
专题北京大学药学院_分子与细胞药理学系
北京大学药学院_药物化学系
作者单位1.Shenzhen Peking Univ, Hong Kong Univ Sci & Technol, Ctr Med, Shenzhen 518036, Peoples R China
2.Peking Univ, Dept Med Chem, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China
3.Peking Univ, Sch Pharmaceut Sci, PKU IDG McGovern Inst Brain Res, Dept Mol & Cellular Pharmacol, Beijing 100050, Peoples R China
4.Qingdao Univ, Sch Pharm, Dept Pharmacol, Qingdao 266021, Peoples R China
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GB/T 7714
Tang, Jing-shu,Xie, Bing-xue,Bian, Xi-ling,et al. Identification and in vitro pharmacological characterization of a novel and selective alpha 7 nicotinic acetylcholine receptor agonist, Br-IQ17B[J]. ACTA PHARMACOLOGICA SINICA,2015,36(7):800-812.
APA Tang, Jing-shu.,Xie, Bing-xue.,Bian, Xi-ling.,Xue, Yu.,Wei, Ning-ning.,...&Wang, Ke-wei.(2015).Identification and in vitro pharmacological characterization of a novel and selective alpha 7 nicotinic acetylcholine receptor agonist, Br-IQ17B.ACTA PHARMACOLOGICA SINICA,36(7),800-812.
MLA Tang, Jing-shu,et al."Identification and in vitro pharmacological characterization of a novel and selective alpha 7 nicotinic acetylcholine receptor agonist, Br-IQ17B".ACTA PHARMACOLOGICA SINICA 36.7(2015):800-812.
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