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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

AuthorsPérez de Vega, M. Jesús; Fernández-Mendívil, Cristina; Torre Martínez, R. de la; González-Rodríguez, Sara; Mullet, José; Sala, Francisco; Sala, Salvador; Criado, Manuel CSIC ORCID; Moreno-Fernández, Silvia; Miguel, Marta CSIC ORCID ; Fernández-Carvajal, Asia; Ferrer-Montiel, Antonio; López, Manuela G.; González-Muñiz, Rosario CSIC ORCID
α7 Nicotinic receptors
Allosteric modulation
Alzheimer disease
Issue Date2019
PublisherAmerican Chemical Society
CitationACS Chemical Neuroscience 10: 3900-3909 (2019)
AbstractAcetylcholine 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 Aβ, 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.
Publisher version (URL)http://dx.doi.org/10.1021/acschemneuro.9b00364
Identifiersdoi: 10.1021/acschemneuro.9b00364
issn: 1948-7193
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