Cytoprotective Effect of Afobazole and Its Main Metabolite M-11

Kadnikov, I. A.; Voronin, M. V.; Seredenin, S. B.

doi:10.1007/s10517-015-2886-9

Cited by 7 publications

(12 citation statements)

References 11 publications

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“…More pronounced cytoprotective effect of afobazole as compared with PRE‐084 corresponds to concept of multitarget mechanism of the drug action and presumably achieved by additive effects of SigmaR1 and MT 3 (Kadnikov et al. ).…”

Section: Discussionmentioning

confidence: 99%

“…Mechanisms of cytoprotective action of afobazole were studied using previously described model of menadione genotoxicity (Kadnikov et al. ; Woods et al. ).…”

Section: Methodsmentioning

confidence: 99%

“…We utilized SCGE‐assay (comet assay) to evaluate DNA damage in mouse bone marrow cells exposed to menadione as a marker of oxidative stress in vitro (Kadnikov et al. ). We found that in this model M‐11 possess less cytoprotective potential than afobazole.…”

Section: Introductionmentioning

confidence: 99%

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Contribution of Sigma‐1 receptor to cytoprotective effect of afobazole

Voronin

Kadnikov

2016

Pharmacol Res Perspect

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Anxiolytic afobazole (5‐Ethoxy‐2‐[2‐(morpholino)‐ethylthio]benzimidazole dihidrochloride) has pronounced ligand properties toward Sigma‐1 receptor (σ1 receptor,SigmaR1) and MT 3 receptors. Our previous work demonstrated that afobazole possess cytoprotective effect in the in vitro model of menadione genotoxicity (Woods et al. 1997) through interaction with MT 3 receptor (Kadnikov et al. 2014). Present study utilized previously described models to address the contribution of SigmaR1 to cytoprotective action of afobazole. The reduction in afobazole cytoprotective effect observed after preincubation of cell suspension with selective SigmaR1 antagonist BD‐1047 revealed an important contribution of SigmaR1 in afobazole‐mediated effect. We confirmed our observation using selective SigmaR1 agonist PRE‐084. We conclude that pronounced cytoprotective effect of afobazole over PRE‐084 is likely achieved by additive SigmaR1 and MT 3‐mediated effects.

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Section: Discussionmentioning

confidence: 99%

“…Mechanisms of cytoprotective action of afobazole were studied using previously described model of menadione genotoxicity (Kadnikov et al. ; Woods et al. ).…”

Section: Methodsmentioning

confidence: 99%

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Contribution of Sigma‐1 receptor to cytoprotective effect of afobazole

Voronin

Kadnikov

2016

Pharmacol Res Perspect

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“…Some studies performed on Afobazole metabolites revealed that one of them, M-11, can bind the MT 3 receptor (K i = 0.39 µM) with a slightly higher affinity, while a lower affinity is associated to the MT 1 receptor (K i = 44 µM). Consequently, Afobazole activity can be considered empowered by the additive activity of its metabolite M-11 (Figure 11) [124].…”

Section: Mtdls Acting At σ 1 Nmda Receptors and Vgccmentioning

confidence: 99%

“…With this in mind, Garcia et al developed a heterogeneous class of ligands with the aim to reinforce the antinociceptive activity mediated by µ-opioid receptor (MOR) agonists with an antagonist activity at the σ 1 receptor that has a well-established role in the treatment of pain. Some pieces of evidence have demonstrated that the antagonist S1RA [124,127] is able to potentiate morphine antinociceptive activity without increasing side effects, so that it entered clinical trials for treating different kinds of pain [135,136].…”

Section: Mtdls Acting At σ 1 and µ-Opioid Receptorsmentioning

confidence: 99%

Multi-Target Directed Ligands (MTDLs) Binding the σ1 Receptor as Promising Therapeutics: State of the Art and Perspectives

Abatematteo

Niso

Contino

et al. 2021

IJMS

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The sigma-1 (σ1) receptor is a ‘pluripotent chaperone’ protein mainly expressed at the mitochondria–endoplasmic reticulum membrane interfaces where it interacts with several client proteins. This feature renders the σ1 receptor an ideal target for the development of multifunctional ligands, whose benefits are now recognized because several pathologies are multifactorial. Indeed, the current therapeutic regimens are based on the administration of different classes of drugs in order to counteract the diverse unbalanced physiological pathways associated with the pathology. Thus, the multi-targeted directed ligand (MTDL) approach, with one molecule that exerts poly-pharmacological actions, may be a winning strategy that overcomes the pharmacokinetic issues linked to the administration of diverse drugs. This review aims to point out the progress in the development of MTDLs directed toward σ1 receptors for the treatment of central nervous system (CNS) and cancer diseases, with a focus on the perspectives that are proper for this strategy. The evidence that some drugs in clinical use unintentionally bind the σ1 protein (as off-target) provides a proof of concept of the potential of this strategy, and it strongly supports the promise that the σ1 receptor holds as a target to be hit in the context of MTDLs for the therapy of multifactorial pathologies.

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Molecular Pharmacology of NRH:Quinone Oxidoreductase 2: A Detoxifying Enzyme Acting as an Undercover Toxifying Enzyme

et al. 2020

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N-ribosyldihydronicotinamide:quinone oxidoreductase 2 (NQO2/ QR2, Enzyme Commission number 1.10.99.2) is a cytosolic enzyme, abundant in the liver and variably expressed in mammalian tissues. Cloned 30 years ago, it was characterized as a flavoenzyme catalyzing the reduction of quinones and pseudoquinones. To do so, it uses exclusively N-alkyl nicotinamide derivatives, without being able to recognize NADH, the reference hydrure donor compound, in contrast to its next of a kind, NAD(P)H:quinone oxidoreductase 1 (NQO1). For a long time both enzymes have been considered as key detoxifying enzymes in quinone metabolism, but more recent findings point to a more toxifying function of NQO2, particularly with respect to ortho-quinones. In fact, during the reduction of substrates, NQO2 generates fairly unstable intermediates that reoxidize immediately back to the original quinone, creating a futile cycle, the byproducts of which are deleterious reactive oxygen species. Beside this peculiarity, it is a target for numerous drugs and natural compounds such as melatonin, chloroquine, imiquimod, resveratrol, piceatannol, *

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Cytoprotective Effect of Afobazole and Its Main Metabolite M-11

Cited by 7 publications

References 11 publications

Contribution of Sigma‐1 receptor to cytoprotective effect of afobazole

Contribution of Sigma‐1 receptor to cytoprotective effect of afobazole

Multi-Target Directed Ligands (MTDLs) Binding the σ1 Receptor as Promising Therapeutics: State of the Art and Perspectives

Molecular Pharmacology of NRH:Quinone Oxidoreductase 2: A Detoxifying Enzyme Acting as an Undercover Toxifying Enzyme

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