变构调节剂
神经保护
药理学
化学
受体
烟碱激动剂
兴奋剂
乙酰胆碱受体
变构调节
毒蕈碱乙酰胆碱受体
止痛药
烟碱乙酰胆碱受体
生物化学
生物
作者
M. Jesús Pérez de Vega,Cristina Fernández‐Mendívil,Rafael Giménez Martínez,Sara González-Rodríguez,José Mullet,Francisco Sala,Salvador Sala,Manuel Criado,Silvia Moreno-Fernández,Marta Miguel,Asia Fernández-Carvajal,Antonio Ferrer-Montiel,Manuela G. López,Rosario González‐Muñiz
标识
DOI:10.1021/acschemneuro.9b00364
摘要
Acetylcholine α7 nicotinic receptors are widely expressed in the brain, where they are involved in the central processing of pain as well as in neuropsychiatric, neurodegenerative, and inflammatory processes. Positive allosteric modulators (PAMs) show the advantage of allowing the selective regulation of different subtypes of acetylcholine receptors without directly interacting with the agonist binding site. Here, we report the preparation and biological activity of a fluoro-containing compound, 1-(2',5'-dihydroxyphenyl)-3-(2-fluoro-4-hydroxyphenyl)-1-propanone (8, RGM079), that behaves as a potent PAM of the α7 receptors and has a balanced pharmacokinetic profile and antioxidant properties comparable or even higher than well-known natural polyphenols. In addition, compound RGM079 shows neuroprotective properties in Alzheimer's disease (AD)-toxicity related models. Thus, it causes a concentration-dependent neuroprotective effect against the toxicity induced by okadaic acid (OA) in the human neuroblastoma cell line SH-SY5Y. Similarly, in primary cultures of rat cortical neurons, RGM079 is able to restore the cellular viability after exposure to OA and amyloid peptide Aβ1-42, with cell death almost completely prevented at 10 and 30 μM, respectively. Finally, compound RGM079 shows in vivo analgesic activity in the complete Freund's adjuvant (CFA)-induced paw inflammation model after intraperitoneal administration.
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