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学科主题: 药学
题名:
Identification and in vitro pharmacological characterization of a novel and selective alpha 7 nicotinic acetylcholine receptor agonist, Br-IQ17B
作者: 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
发表日期: 2015-07-01
DOI: 10.1038/aps.2015.9
卷: 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
所属项目编号: 2013CB531302 ; 2014ZX09507003-006-004 ; 31370741 ; 81221002 ; 81373272
项目资助者: Ministry of Science and Technology of China ; National Natural Science Foundation of China ; Beijing Higher Education Young Elite Teacher Project
WOS记录号: WOS:000357477600004
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/62534
Appears in Collections:北京大学药学院_药物化学系_期刊论文

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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

Recommended Citation:
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.
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