title: Identification and in vitro pharmacological characterization of a novel and selective α7 nicotinic acetylcholine receptor agonist, Br-IQ17B.
abstract: OBJECTIVE
  Alpha7-nicotinic acetylcholine receptor (α7 nAChR) is a ligand-gated Ca(2+)-permeable ion channel implicated in cognition and neuropsychiatric disorders. Activation of α7 nAChR improves learning, memory, and sensory gating in animal models. To identify novel α7 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 α7 nAChR.
  
  
  METHODS
  Two-electrode voltage clamp (TEVC) recordings were primarily used for screening in Xenopus oocytes expressing human α7 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 α7 nAChR by Br-IQ17B.
  
  
  RESULTS
  Br-IQ17B potently activates α7 nAChR with an EC50 of 1.8±0.2 μmol/L. Br-IQ17B is selective over other subtypes such as α4β2 and α3β4, but it blocks 5-HT3A receptors. Br-IQ17B displaced binding of the α7 blocker [(3)H]-MLA to hippocampal crude membranes with a Ki of 14.9±3.2 nmol/L. In hippocampal neurons, Br-IQ17B evoked α7-like currents that were inhibited by MLA and enhanced in the presence of the α7 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.
  
  
  CONCLUSIONS
  We identified the novel, potent, and selective α7 agonist Br-IQ17B, which enhances synaptic transmission. Br-IQ17B may be a helpful tool to understand new aspects of α7 nAChR function, and it also has potential for being developed as therapy for schizophrenia and cognitive deficits.
authors.affiliation: Shenzhen-Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen 518036, China.
authors.forename: Jing-shu
authors.initials: JS
authors.lastname: Tang
authors.affiliation: Department of Medicinal Chemistry, State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China.
authors.forename: Bing-xue
authors.initials: BX
authors.lastname: Xie
authors.affiliation: Department of Molecular and Cellular Pharmacology, PKU-IDG/McGovern Institute for Brain Research, Peking University School of Pharmaceutical Sciences, Beijing 100050, China.
authors.forename: Xi-ling
authors.initials: XL
authors.lastname: Bian
authors.affiliation: Department of Medicinal Chemistry, State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Xue
authors.affiliation: Department of Molecular and Cellular Pharmacology, PKU-IDG/McGovern Institute for Brain Research, Peking University School of Pharmaceutical Sciences, Beijing 100050, China.
authors.forename: Ning-ning
authors.initials: NN
authors.lastname: Wei
authors.affiliation: Department of Molecular and Cellular Pharmacology, PKU-IDG/McGovern Institute for Brain Research, Peking University School of Pharmaceutical Sciences, Beijing 100050, China.
authors.forename: Jing-heng
authors.initials: JH
authors.lastname: Zhou
authors.affiliation: Department of Molecular and Cellular Pharmacology, PKU-IDG/McGovern Institute for Brain Research, Peking University School of Pharmaceutical Sciences, Beijing 100050, China.
authors.forename: Yu-chen
authors.initials: YC
authors.lastname: Hao
authors.affiliation: Shenzhen-Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen 518036, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Medicinal Chemistry, State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China.
authors.forename: Liang-ren
authors.initials: LR
authors.lastname: Zhang
authors.affiliation: 1] Shenzhen-Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen 518036, China [2] Department of Medicinal Chemistry, State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China [3] Department of Molecular and Cellular Pharmacology, PKU-IDG/McGovern Institute for Brain Research, Peking University School of Pharmaceutical Sciences, Beijing 100050, China [4] Department of Pharmacology, Qingdao University School of Pharmacy, Qingdao 266021, China.
authors.forename: Ke-wei
authors.initials: KW
authors.lastname: Wang
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005260:Female; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008297:Male; D018722:Nicotinic Agonists / Q000737:chemistry* / Q000494:pharmacology*; D009924:Organ Culture Techniques; D016716:PC12 Cells; D051381:Rats; D017207:Rats, Sprague-Dawley; D014982:Xenopus laevis; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000819:agonists* / Q000502:physiology
chemical_list: D018722:Nicotinic Agonists; D064569:alpha7 Nicotinic Acetylcholine Receptor