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

Abstract

Acetylcholine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 (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 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 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 M, respectively. Finally, compound RGM079 shows in vivo analgesic activity in the CFA-induced paw inflammation model, after intraperitoneal administration.

Natural Polyhydroxy Flavonoids, Curcuminoids, and Synthetic Curcumin Analogs as α7 nAChRs Positive Allosteric Modulators

“…This finding led to the evaluation of a collection of chalcones and related compounds, leading to the discovery of two new families of potent PAMs of the α7 nicotinic channels-polyhydroxychalcones [18] and polyhydroxydiphenyl propanones. This permitted the identification of a new chemotype of α7 nAChRs PAMs and compounds that exhibit promising analgesic and neuroprotective activities [19][20][21].…”

Drug Development in Channelopathies: Allosteric Modulation of Ligand-Gated and Voltage-Gated Ion Channels

“…RGM079 is another α7 nAChR PAM, which potentiated ACh-evoked currents without acting as an agonist in the absence of ACh. 42 Interestingly, ACh-induced currents in the presence of RGM079 decayed in a biphasic manner with a slow deactivation rate following a fast decay, indicative of RGM079 acting as a type I and type II α7 nAChR PAM. Further studies revealed that RGM079 was a promising drug candidate with acceptable pharmacokinetic properties, in vitro antioxidant and neuroprotective activities, and in vivo analgesic effect.…”

“…Thus, B-973 functions as a type II PAM of α7 nAChRs and also as an allosteric agonist at high concentrations. RGM079 is another α7 nAChR PAM, which potentiated ACh-evoked currents without acting as an agonist in the absence of ACh . Interestingly, ACh-induced currents in the presence of RGM079 decayed in a biphasic manner with a slow deactivation rate following a fast decay, indicative of RGM079 acting as a type I and type II α7 nAChR PAM.…”

Synthesis and Biological Evaluation of Novel Triazine Derivatives as Positive Allosteric Modulators of α7 Nicotinic Acetylcholine Receptors

“…In a clinical trial of phase 1b in 24 subjects with schizophrenia or schizoaffective disorder, AVL-3288 shows a lack of clinical effect. 13d Novel 3a (JNJ-1930942, mixed type I/II PAM, Figure 1), 15 3b (RGM079, mixed type I/II PAM, Figure 1), 16 and piperazine 4 (B-973, Ago-PAM, Figure 1) 17 were successively reported for the purpose of improved pharmacological activities in recent years. In addition, compound 1d is carried phase 1 clinical study (ref 9).…”