1-(2′,5′-Dihydroxyphenyl)-3-(2-fluoro-4-hydroxyphenyl)-1-propanone (RGM079): A Positive Allosteric Modulator of α7 Nicotinic Receptors with Analgesic and Neuroprotective Activity

被引:14
|
作者
Perez de Vega, Maria Jesus [1 ]
Fernandez-Mendivil, Cristina [2 ]
de la Torre Martinez, Roberto [3 ]
Gonzalez-Rodriguez, Sara [3 ]
Mullet, Jose [4 ]
Sala, Francisco [4 ]
Sala, Salvador [4 ]
Criado, Manuel [4 ]
Moreno-Fernandez, Silvia [5 ]
Miguel, Marta [5 ]
Fernandez-Carvajal, Asia [3 ]
Ferrer-Montie, Antonio [3 ]
Lopez, Manuela G. [2 ]
Gonzalez-Muniz, Rosario [1 ]
机构
[1] CSIC, IQM, Juan de la Cierva 3, Madrid 28006, Spain
[2] Univ Autonoma Madrid, Dept Pharmacol, Inst Teofilo Hernando, Arzobispo Morcillo 4, E-28049 Madrid 28029, Spain
[3] Univ Miguel Hernandez, Inst Invest Desarrollo & Innovac Biotecnol Sanita, Alicante 03202, Spain
[4] Univ Miguel Hernandez, CSIC, Inst Neurociencias, Alicante 03500, Spain
[5] UAM, CSIC, Inst Invest Ciencias Alimentac, C Nicolis Cabrera 9, Madrid 28049, Spain
来源
ACS CHEMICAL NEUROSCIENCE | 2019年 / 10卷 / 08期
关键词
Diphenylpropanones; alpha 7 nicotinic receptors; allosteric modulation; neuroprotection; analgesia; Alzheimer's disease; ACETYLCHOLINE-RECEPTORS; ANTIOXIDANT ACTIVITY; OKADAIC ACID; NACHR; GALANTAMINE; CAPACITY; AGONISTS; NEUROINFLAMMATION; FLUORESCEIN; MELATONIN;
D O I
10.1021/acschemneuro.9b00364
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Acetylcholine alpha 7 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 alpha 7 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-SYSY. Similarly, in primary cultures of rat cortical neurons, RGM079 is able to restore the cellular viability after exposure to OA and amyloid peptide A beta(1-42), with cell death almost completely prevented at 10 and 30 mu M, respectively. Finally, compound RGM079 shows in vivo analgesic activity in the complete Freund's adjuvant (CFA)-induced paw inflammation model after intraperitoneal administration.
引用
收藏
页码:3900 / 3909
页数:19
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