TY - JOUR AU - Tang Jing-shu AU - Xie Bing-xue AU - Bian Xi-ling AU - Xue Yu AU - Wei Ning-ning AU - Zhou Jing-heng AU - Hao Yu-chen AU - Li Gang AU - Zhang Liang-ren AU - Wang Ke-wei PY - 2017 TI - Identification and in vitro pharmacological characterization of a novel and selective α7 nicotinic acetylcholine receptor agonist, Br-IQ17B JF - Acta Pharmacologica Sinica; Vol 36, No 7 (July 2015): Acta Pharmacologica Sinica Y2 - 2017 KW - N2 - Aim: Alpha7-nicotinic acetylcholine receptor ( α 7 nAChR) is a ligand-gated Ca 2+ -permeable ion channel implicated in cognition and neuropsychiatric disorders. Activation of α 7 nAChR improves learning, memory, and sensory gating in animal models. To identify novel α 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 α 7 nAChR. Methods: Two-electrode voltage clamp (TEVC) recordings were primarily used for screening in Xenopus oocytes expressing human α 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 α 7 nAChR by Br-IQ17B. Results: Br-IQ17B potently activates α 7 nAChR with an EC 50 of 1.8±0.2 μmol/L. Br-IQ17B is selective over other subtypes such as α 4β2 and α 3β4, but it blocks 5-HT 3A receptors. Br-IQ17B displaced binding of the α 7 blocker [ 3 H]-MLA to hippocampal crude membranes with a K i of 14.9±3.2 nmol/L. In hippocampal neurons, Br-IQ17B evoked α 7-like currents that were inhibited by MLA and enhanced in the presence of the α 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 α 7 agonist Br-IQ17B, which enhances synaptic transmission. Br-IQ17B may be a helpful tool to understand new aspects of α 7 nAChR function, and it also has potential for being developed as therapy for schizophrenia and cognitive deficits. UR - http://www.chinaphar.com/article/view/9352