1,3-Diphenylpropan-1-Ones as Allosteric Modulators of α7 Nach Receptors with Analgesic and Antioxidant Properties

Criado, Manuel; Balsera, Beatriz; Mulet, José; Sala, Salvador; Sala, Francisco; Martínez, Rafael Giménez; Fernández-Carvajal, Asia; Ferrer-Montiel, Antonio; Moreno-Fernández, Silvia; Miguel, Marta; Vega, M. Jesús Pérez de; González‐Muñiz, Rosario

doi:10.4155/fmc-2015-0001

Cited by 13 publications

(30 citation statements)

References 52 publications

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“…Furthermore, GTS-21 suppressed cisplatin-mediated glutathione depletion ( Fig 5B ) and ROS formation ( Fig 5C ) in renal epithelial cells. Revealing the antioxidant property of GTS-21 is a novel finding, which corroborates the antioxidant property of other α7nAChR agonists [ 60 – 62 ]. These observations support improved mitochondrial function with GTS-21 treatment in this model but require additional studies to shed more light into the downstream effectors of GTS-21.…”

Section: Discussionsupporting

confidence: 58%

Activation of the cholinergic anti-inflammatory pathway by GTS-21 attenuates cisplatin-induced acute kidney injury in mice

et al. 2017

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Acute kidney injury (AKI) is the most common side effect of cisplatin, a widely used chemotherapy drug. Although AKI occurs in up to one third of cancer patients receiving cisplatin, effective renal protective strategies are lacking. Cisplatin targets renal proximal tubular epithelial cells leading to inflammation, reactive oxygen species, tubular cell injury, and eventually cell death. The cholinergic anti-inflammatory pathway is a vagus nerve-mediated reflex that suppresses inflammation via α7 nicotinic acetylcholine receptors (α7nAChRs). Our previous studies demonstrated the renoprotective and anti-inflammatory effects of cholinergic agonists, including GTS-21. Therefore, we examined the effect of GTS-21 on cisplatin-induced AKI. Male C57BL/6 mice received either saline or GTS-21 (4mg/kg, i.p.) twice daily for 4 days before cisplatin and treatment continued through euthanasia; 3 days post-cisplatin mice were euthanized and analyzed for markers of renal injury. GTS-21 significantly reduced cisplatin-induced renal dysfunction and injury (p<0.05). GTS-21 significantly attenuated renal Ptgs2/COX-2 mRNA and IL-6, IL-1β, and CXCL1 protein expression, as well as neutrophil infiltration after cisplatin. GTS-21 blunted cisplatin-induced renal ERK1/2 activation, as well as renal ATP depletion and apoptosis (p<0.05). GTS-21 suppressed the expression of CTR1, a cisplatin influx transporter and enhanced the expression of cisplatin efflux transporters MRP2, MRP4, and MRP6 (p<0.05). Using breast, colon, and lung cancer cell lines we showed that GTS-21 did not inhibit cisplatin’s tumor cell killing activity. GTS-21 protects against cisplatin-AKI by attenuating renal inflammation, ATP depletion and apoptosis, as well as by decreasing renal cisplatin influx and increasing efflux, without impairing cisplatin-mediated tumor cell killing. Our results support further exploring the cholinergic anti-inflammatory pathway for preventing cisplatin-induced AKI.

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Section: Discussionsupporting

confidence: 58%

Activation of the cholinergic anti-inflammatory pathway by GTS-21 attenuates cisplatin-induced acute kidney injury in mice

et al. 2017

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“…Interestingly, compound 111 exerted analgesic activity in CFA-injected rats (Balsera et al, 2014). Further work studied the compound 31, which displayed an improved potentiation (≈666%, 10 mM of compound) of a7nAChRs-mediated currents (Criado et al, 2016). In CFA-injected rats, the compound 31 displayed analgesic effects similar to those obtained with PNU-120596 (Criado et al, 2016).…”

Section: -Ht 3 Rsmentioning

confidence: 77%

“…Further work studied the compound 31, which displayed an improved potentiation (≈666%, 10 mM of compound) of a7nAChRs-mediated currents (Criado et al, 2016). In CFA-injected rats, the compound 31 displayed analgesic effects similar to those obtained with PNU-120596 (Criado et al, 2016). However, these chalcone-derivate compounds have low aqueous solubility and short time of action in vivo (Balsera et al, 2018).…”

Section: -Ht 3 Rsmentioning

confidence: 93%

“…Interestingly, these effects were not observed in a7 nAChR knock-out mice and were blocked by the a7nAChR antagonist MLA (Papke et al, 2015). A systematic screening of a library of small natural molecules (Greenpharma Natural compound library, Prestwick Chemical, France) combined with structure-activity relationship analysis lead to the discovery of hydroxylated chalcones as new PAMs targeting a7nAChRs (Balsera et al, 2014;Criado et al, 2016;Balsera et al, 2018). The compound 111 was characterized as a selective a7nAChR PAM (EC 50 ≈3 mM) by using two-electrode voltage-clamp (TEVC) recordings in Xenopus oocytes.…”

Section: -Ht 3 Rsmentioning

confidence: 99%

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Pentameric Ligand-Gated Ion Channels as Pharmacological Targets Against Chronic Pain

et al. 2020

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Chronic pain is a common detrimental condition that affects around 20% of the world population. The current drugs to treat chronic pain states, especially neuropathic pain, have a limited clinical efficiency and present significant adverse effects that complicates their regular use. Recent studies have proposed new therapeutic strategies focused on the pharmacological modulation of G-protein-coupled receptors, transporters, enzymes, and ion channels expressed on the nociceptive pathways. The present work intends to summarize recent advances on the pharmacological modulation of pentameric ligandgated ion channels, which plays a key role in pain processing. Experimental data have shown that novel allosteric modulators targeting the excitatory nicotinic acetylcholine receptor, as well as the inhibitory GABA A and glycine receptors, reverse chronic painrelated behaviors in preclinical assays. Collectively, these evidences strongly suggest the pharmacological modulation of pentameric ligand-gated ion channels is a promising strategy towards the development of novel therapeutics to treat chronic pain states in humans.

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“…A brief in vitro study of the pharmacokinetic (PK) properties of compounds 1-3 ( Figure 1) revealed a quite poor PK profile, limiting their therapeutic potential. 31 These results prompted us to synthesize new analogues to improve the pharmacokinetic properties. In this sense, we have recently described the preparation of peptide pro-drugs of some diphenyl propanones with the aim of increasing the in vivo efficacy of the parent drugs, 2 and 3, endowed with longer-lasting effects than their parent drugs.…”

Section: Introductionmentioning

confidence: 99%

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

Vega

Fernández‐Mendívil

Martínez

et al. 2019

ACS Chem. Neurosci.

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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.

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1,3-Diphenylpropan-1-Ones as Allosteric Modulators of α7 Nach Receptors with Analgesic and Antioxidant Properties

Abstract: Compound 31 is a novel, potent and selective α7 nAChR PAM, displaying antioxidant and analgesic activities. The 1,3-diphenylpropan-1-one scaffold could be the base toward more advanced type I PAMs for the treatment of nAChR-mediated diseases.

Cited by 13 publications

References 52 publications

Activation of the cholinergic anti-inflammatory pathway by GTS-21 attenuates cisplatin-induced acute kidney injury in mice

Activation of the cholinergic anti-inflammatory pathway by GTS-21 attenuates cisplatin-induced acute kidney injury in mice

Pentameric Ligand-Gated Ion Channels as Pharmacological Targets Against Chronic Pain

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

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