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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

  • María Jesús Pérez de Vega*
    María Jesús Pérez de Vega
    Instituto de Química Médica, IQM-CSIC, Juan de la Cierva 3, Madrid 28006, Spain
    *E-mail: [email protected]. Phone: +34915622900. Fax: +34915644853 (M.J.P.d.V.).
  • Cristina Fernandez-Mendivil
    Cristina Fernandez-Mendivil
    Instituto Teófilo Hernando, Department of Pharmacology, Universidad Autónoma de Madrid, Arzobispo Morcillo 4, Madrid 28029, Spain
  • Roberto de la Torre Martínez
    Roberto de la Torre Martínez
    Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, Avenida de la Universidad s/n, Elche, Alicante 03202, Spain
  • Sara González-Rodríguez
    Sara González-Rodríguez
    Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, Avenida de la Universidad s/n, Elche, Alicante 03202, Spain
  • José Mullet
    José Mullet
    Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, Sant Joan d’Alacant, Alicante 03500, Spain
    More by José Mullet
  • Francisco Sala
    Francisco Sala
    Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, Sant Joan d’Alacant, Alicante 03500, Spain
  • Salvador Sala
    Salvador Sala
    Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, Sant Joan d’Alacant, Alicante 03500, Spain
  • Manuel Criado
    Manuel Criado
    Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, Sant Joan d’Alacant, Alicante 03500, Spain
  • Silvia Moreno-Fernández
    Silvia Moreno-Fernández
    Instituto de Investigación en Ciencias de la Alimentación (CSIC-UAM), C/Nicolás Cabrera 9, Madrid 28049, Spain
  • Marta Miguel
    Marta Miguel
    Instituto de Investigación en Ciencias de la Alimentación (CSIC-UAM), C/Nicolás Cabrera 9, Madrid 28049, Spain
    More by Marta Miguel
  • Asia Fernández-Carvajal
    Asia Fernández-Carvajal
    Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, Avenida de la Universidad s/n, Elche, Alicante 03202, Spain
  • Antonio Ferrer-Montiel
    Antonio Ferrer-Montiel
    Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, Avenida de la Universidad s/n, Elche, Alicante 03202, Spain
  • Manuela G. López
    Manuela G. López
    Instituto Teófilo Hernando, Department of Pharmacology, Universidad Autónoma de Madrid, Arzobispo Morcillo 4, Madrid 28029, Spain
  • , and 
  • Rosario González-Muñiz*
    Rosario González-Muñiz
    Instituto de Química Médica, IQM-CSIC, Juan de la Cierva 3, Madrid 28006, Spain
    *E-mail: [email protected]. Phone: +34915622900. Fax: +34915644853 (R.G.-M.).
Cite this: ACS Chem. Neurosci. 2019, 10, 8, 3900–3909
Publication Date (Web):July 19, 2019
https://doi.org/10.1021/acschemneuro.9b00364
Copyright © 2019 American Chemical Society
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Supporting Info (1)»

Abstract

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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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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acschemneuro.9b00364.

  • Methods for the ADME-Tox study and coincubation experiment with OA in SH-Y5S5 cells (PDF)

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Cited By

This article is cited by 7 publications.

  1. Jiaru Li, Junzu Shi, Chenyang Jia, Wei Li, Ying Peng, Jiang Zheng. Metabolic Activation and Cytotoxicity of Propafenone Mediated by CYP2D6. Chemical Research in Toxicology 2022, 35 (5) , 829-839. https://doi.org/10.1021/acs.chemrestox.2c00013
  2. Xintong Wang, Haoran Xiao, Jing Wang, Zongze Huang, Geng Peng, Wenjun Xie, Xiling Bian, Huijie Liu, Cheng Shi, Taoyi Yang, Xin Li, Jian Gao, Ying Meng, Qianchen Jiang, Wei Chen, Fang Hu, Ningning Wei, Xiaowei Wang, Liangren Zhang, KeWei Wang, Qi Sun. Synthesis and Biological Evaluation of Novel Triazine Derivatives as Positive Allosteric Modulators of α7 Nicotinic Acetylcholine Receptors. Journal of Medicinal Chemistry 2021, 64 (16) , 12379-12396. https://doi.org/10.1021/acs.jmedchem.1c01058
  3. Yanyun Zhang, Ke Wang, Zhiyi Yu. Drug Development in Channelopathies: Allosteric Modulation of Ligand-Gated and Voltage-Gated Ion Channels. Journal of Medicinal Chemistry 2020, 63 (24) , 15258-15278. https://doi.org/10.1021/acs.jmedchem.0c01304
  4. Roger L. Papke, Nicole A. Horenstein, . Therapeutic Targeting of α 7 Nicotinic Acetylcholine Receptors. Pharmacological Reviews 2021, 73 (3) , 1118-1149. https://doi.org/10.1124/pharmrev.120.000097
  5. Marta Ximenis, José Mulet, Salvador Sala, Francisco Sala, Manuel Criado, Rosario González-Muñiz, María Jesús Pérez de Vega. Natural Polyhydroxy Flavonoids, Curcuminoids, and Synthetic Curcumin Analogs as α7 nAChRs Positive Allosteric Modulators. International Journal of Molecular Sciences 2021, 22 (2) , 973. https://doi.org/10.3390/ijms22020973
  6. Miwa Takatsuka, Satoru Goto, Kenshiro Kobayashi, Yuta Otsuka, Yohsuke Shimada. Leading individual features of antioxidant systematically classified by the ORAC assay and its single electron transfer and hydrogen atom transfer reactivities; analyzing ALS therapeutic drug Edaravone. BBA Advances 2021, 1 , 100030. https://doi.org/10.1016/j.bbadva.2021.100030
  7. María Jesús Pérez de Vega, Silvia Moreno-Fernández, Gloria María Pontes-Quero, María González-Amor, Blanca Vázquez-Lasa, Beatriz Sabater-Muñoz, Ana M. Briones, María R. Aguilar, Marta Miguel, Rosario González-Muñiz. Characterization of Novel Synthetic Polyphenols: Validation of Antioxidant and Vasculoprotective Activities. Antioxidants 2020, 9 (9) , 787. https://doi.org/10.3390/antiox9090787

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