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Papers of the Week

Papers: 20 Jul 2019 - 26 Jul 2019

Animal Studies, Pharmacology/Drug Development

2019 Aug 21

ACS Chem Neurosci



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.


Pérez de Vega M J, Fernández-Mendívil C, de la Torre-Martinez R, González-Rodríguez S, Mulet J, Sala F, Sala S, Criado M, Moreno-Fernandez S, Miguel M, Fernández-Carvajal A, Ferrer-Montiel A, López MG, González-Muñiz R
ACS Chem Neurosci. 2019 Aug 21; 10(8):3900-3909.
PMID: 31322853.


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 (PAM) 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 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 CFA-induced paw inflammation model, after intraperitoneal administration.