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1.
Int J Mol Sci ; 22(18)2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34575952

RESUMO

Sigma1 Receptor (S1R) is involved in oxidative stress, since its activation is triggered by oxidative or endoplasmic reticulum stress. Since specific aquaporins (AQP), called peroxiporins, play a relevant role in controlling H2O2 permeability and ensure reactive oxygen species wasted during oxidative stress, we studied the effect of S1R modulators on AQP-dependent water and hydrogen peroxide permeability in the presence and in the absence of oxidative stress. Applying stopped-flow light scattering and fluorescent probe methods, water and hydrogen peroxide permeability in HeLa cells have been studied. Results evidenced that S1R agonists can restore water permeability in heat-stressed cells and the co-administration with a S1R antagonist totally counteracted the ability to restore the water permeability. Moreover, compounds were able to counteract the oxidative stress of HeLa cells specifically knocked down for S1R. Taken together these results support the hypothesis that the antioxidant mechanism is mediated by both S1R and AQP-mediated H2O2 permeability. The finding that small molecules can act on both S1R and AQP-mediated H2O2 permeability opens a new direction toward the identification of innovative drugs able to regulate cell survival during oxidative stress in pathologic conditions, such as cancer and degenerative diseases.


Assuntos
Aquaporinas/metabolismo , Peróxido de Hidrogênio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Receptores sigma/genética , Aquaporinas/genética , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Células HeLa , Humanos , Permeabilidade/efeitos dos fármacos , Peroxirredoxinas/genética , Peroxirredoxinas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores sigma/agonistas , Receptores sigma/metabolismo
2.
Int J Mol Sci ; 22(16)2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34445144

RESUMO

Developmental and epileptic encephalopathies (DEEs) are complex conditions characterized primarily by seizures associated with neurodevelopmental and motor deficits. Recent evidence supports sigma-1 receptor modulation in both neuroprotection and antiseizure activity, suggesting that sigma-1 receptors may play a role in the pathogenesis of DEEs, and that targeting this receptor has the potential to positively impact both seizures and non-seizure outcomes in these disorders. Recent studies have demonstrated that the antiseizure medication fenfluramine, a serotonin-releasing drug that also acts as a positive modulator of sigma-1 receptors, reduces seizures and improves everyday executive functions (behavior, emotions, cognition) in patients with Dravet syndrome and Lennox-Gastaut syndrome. Here, we review the evidence for sigma-1 activity in reducing seizure frequency and promoting neuroprotection in the context of DEE pathophysiology and clinical presentation, using fenfluramine as a case example. Challenges and opportunities for future research include developing appropriate models for evaluating sigma-1 receptors in these syndromic epileptic conditions with multisystem involvement and complex clinical presentation.


Assuntos
Encefalopatias/metabolismo , Síndromes Epilépticas/metabolismo , Receptores sigma/metabolismo , Animais , Anticonvulsivantes/farmacologia , Encefalopatias/tratamento farmacológico , Síndromes Epilépticas/tratamento farmacológico , Fenfluramina/farmacologia , Humanos , Convulsões/tratamento farmacológico , Convulsões/metabolismo
3.
Molecules ; 26(12)2021 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-34205334

RESUMO

Sigma-2 (σ2) is an endoplasmic receptor identified as the Endoplasmic Reticulum (ER) transmembrane protein TMEM97. Despite its controversial identity, which was only recently solved, this protein has gained scientific interest because of its role in the proliferative status of cells; many tumor cells from different organs overexpress the σ2 receptor, and many σ2 ligands display cytotoxic actions in (resistant) cancer cells. These properties have shed light on the σ2 receptor as a potential druggable target to be bound/activated for the diagnosis or therapy of tumors. Additionally, diverse groups have shown how the σ2 receptor can be exploited for the targeted delivery of the anticancer drugs to tumors. As the cancer disease is a multifactorial pathology with multiple cell populations, a polypharmacological approach is very often needed. Instead of the simultaneous administration of different classes of drugs, the use of one molecule that interacts with diverse pharmacological targets, namely MultiTarget Directed Ligand (MTDL), is a promising and currently pursued strategy, that may overcome the pharmacokinetic problems associated with the administration of multiple molecules. This review aims to point out the progress regarding the σ2 ligands in the oncology field, with a focus on MTDLs directed towards σ2 receptors as promising weapons against (resistant) cancer diseases.


Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Receptores sigma/metabolismo , Animais , Proteínas de Transporte/metabolismo , Humanos , Ligantes , Proteínas de Membrana/metabolismo
4.
Int J Mol Sci ; 22(13)2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34203381

RESUMO

Loss of motor neurons (MNs) after spinal root injury is a drawback limiting the recovery after palliative surgery by nerve or muscle transfers. Research based on preventing MN death is a hallmark to improve the perspectives of recovery following severe nerve injuries. Sigma-1 receptor (Sig-1R) is a protein highly expressed in MNs, proposed as neuroprotective target for ameliorating MN degenerative conditions. Here, we used a model of L4-L5 rhizotomy in adult mice to induce MN degeneration and to evaluate the neuroprotective role of Sig-1R ligands (PRE-084, SA4503 and BD1063). Lumbar spinal cord was collected at 7, 14, 28 and 42 days post-injury (dpi) for immunohistochemistry, immunofluorescence and Western blot analyses. This proximal axotomy at the immediate postganglionic level resulted in significant death, up to 40% of spinal MNs at 42 days after injury and showed markedly increased glial reactivity. Sig-1R ligands PRE-084, SA4503 and BD1063 reduced MN loss by about 20%, associated to modulation of endoplasmic reticulum stress markers IRE1α and XBP1. These pathways are Sig-1R specific since they were not produced in Sig-1R knockout mice. These findings suggest that Sig-1R is a promising target for the treatment of MN cell death after neural injuries.


Assuntos
Neurônios Motores/efeitos dos fármacos , Neurônios Motores/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Receptores sigma/agonistas , Receptores sigma/metabolismo , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/metabolismo , Animais , Western Blotting , Feminino , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL
5.
Molecules ; 26(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202711

RESUMO

Cancer is a multifactorial disease that may be tackled by targeting different signaling pathways. Heme oxygenase-1 (HO-1) and sigma receptors (σRs) are both overexpressed in different human cancers, including prostate and brain, contributing to the cancer spreading. In the present study, we investigated whether HO-1 inhibitors and σR ligands, as well a combination of the two, may influence DU145 human prostate and U87MG human glioblastoma cancer cells proliferation. In addition, we synthesized, characterized, and tested a small series of novel hybrid compounds (HO-1/σRs) 1-4 containing the chemical features needed for HO-1 inhibition and σR modulation. Herein, we report for the first time that targeting simultaneously HO-1 and σR proteins may be a good strategy to achieve increased antiproliferative activity against DU145 and U87MG cells, with respect to the mono administration of the parent compounds. The obtained outcomes provide an initial proof of concept useful to further optimize the structure of HO-1/σRs hybrids to develop novel potential anticancer agents.


Assuntos
Antineoplásicos , Inibidores Enzimáticos , Heme Oxigenase-1/antagonistas & inibidores , Proteínas de Neoplasias/antagonistas & inibidores , Neoplasias , Receptores sigma/antagonistas & inibidores , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Heme Oxigenase-1/metabolismo , Humanos , Proteínas de Neoplasias/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Ratos , Receptores sigma/metabolismo
6.
Int J Mol Sci ; 22(12)2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34198620

RESUMO

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.


Assuntos
Receptores sigma/metabolismo , Animais , Humanos , Concentração Inibidora 50 , Ligantes , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Células-Tronco/metabolismo
7.
Eur J Med Chem ; 223: 113658, 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34175542

RESUMO

Opioid analgesics are highly effective painkillers for the treatment of moderate or severe pain, but they are associated with a number of undesirable adverse effects, including the development of tolerance, addiction, constipation and life-threatening respiratory depression. The development of new and safer analgesics with innovative mechanisms of action, which can enhance the efficacy in comparison to available treatments and reduce their side effects, is urgently needed. The sigma-1 receptor (σ1R), a unique Ca2+-sensing chaperone protein, is expressed throughout pain-modulating tissues and affects neurotransmission by interacting with different protein partners, including molecular targets that participate in nociceptive signalling, such as the µ-opioid receptor (MOR), N-methyl-d-aspartate receptor (NMDAR) and cannabinoid 1 receptor (CB1R). Overwhelming pharmacological and genetic evidence indicates that σ1R antagonists induce anti-hypersensitive effects in sensitising pain conditions (e.g. chemically induced, inflammatory and neuropathic pain) and enhance opioid analgesia but not opioid-mediated detrimental effects. It has been suggested that balanced modulation of MORs and σ1Rs may improve both the therapeutic efficacy and safety of opioids. This review summarises the functional profiles of ligands with mixed MOR agonist and σ1R antagonist activities and highlights their therapeutic potentials for pain management. Dual MOR agonism/σ1R antagonism represents a promising avenue for the development of potent and safer analgesics.


Assuntos
Analgésicos Opioides/química , Receptores Opioides delta/antagonistas & inibidores , Receptores Opioides mu/agonistas , Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/metabolismo , Analgésicos Opioides/uso terapêutico , Benzopiranos/química , Benzopiranos/metabolismo , Humanos , Ligantes , Dor/tratamento farmacológico , Piperazinas/química , Piperazinas/metabolismo , Receptores Opioides delta/metabolismo , Receptores Opioides mu/metabolismo , Receptores sigma/antagonistas & inibidores , Receptores sigma/metabolismo
8.
Invest Ophthalmol Vis Sci ; 62(7): 5, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34086045

RESUMO

Purpose: Stimulation of Sigma 1 Receptor (S1R) is neuroprotective in retina and optic nerve. S1R is expressed in both neurons and glia. The purpose of this work is to evaluate the ability of S1R to modulate reactivity responses of optic nerve head astrocytes (ONHAs) by investigating the extent to which S1R activation alters ONHA reactivity under conditions of ischemic cellular stress. Methods: Wild type (WT) and S1R knockout (KO) ONHAs were derived and treated with vehicle or S1R agonist, (+)-pentazocine ((+)-PTZ). Cells were subjected to six hours of oxygen glucose deprivation (OGD) followed by 18 hours of re-oxygenation (OGD/R). Astrocyte reactivity responses were measured. Molecules that regulate ONHA reactivity, signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappa B (NF-kB), were evaluated. Results: Baseline glial fibrillary acidic protein (GFAP) levels were increased in nonstressed KO ONHAs compared with WT cultures. Baseline cellular migration was also increased in nonstressed KO ONHAs compared with WT. Treatment with (+)-PTZ increased cellular migration in nonstressed WT ONHAs but not in KO ONHAs. Exposure of both WT and KO ONHAs to ischemia (OGD/R), increased GFAP levels and cellular proliferation. However, (+)-PTZ treatment of OGD/R-exposed ONHAs enhanced GFAP levels, cellular proliferation, and cellular migration in WT but not KO cultures. The (+)-PTZ treatment of WT ONHAs also enhanced the OGD/R-induced increase in cellular pSTAT3 levels. However, treatment of WT ONHAs with (+)-PTZ abrogated the OGD/R-induced rise in NF-kB(p65) activation. Conclusions: Under ischemic stress conditions, S1R activation enhanced ONHA reactivity characteristics. Future studies should address effects of these responses on RGC survival.


Assuntos
Astrócitos/metabolismo , Disco Óptico , Receptores sigma , Células Ganglionares da Retina/metabolismo , Animais , Células Cultivadas , Camundongos , Camundongos Knockout , Neuroproteção/fisiologia , Fármacos Neuroprotetores/farmacologia , Disco Óptico/metabolismo , Disco Óptico/patologia , Neuropatia Óptica Isquêmica/metabolismo , Pentazocina/farmacologia , Receptores sigma/agonistas , Receptores sigma/metabolismo , Resultado do Tratamento
9.
Int J Mol Sci ; 22(10)2021 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-34068146

RESUMO

Orexin A, an endogenous peptide involved in several functions including reward, acts via activation of orexin receptors OX1 and OX2, Gq-coupled GPCRs. We examined the effect of a selective OX1 agonist, OXA (17-33) on cytosolic calcium concentration, [Ca2+]i, in neurons of nucleus accumbens, an important area in the reward circuit. OXA (17-33) increased [Ca2+]i in a dose-dependent manner; the effect was prevented by SB-334867, a selective OX1 receptors antagonist. In Ca2+-free saline, the OXA (17-33)-induced increase in [Ca2+]i was not affected by pretreatment with bafilomycin A1, an endo-lysosomal calcium disrupter, but was blocked by 2-APB and xestospongin C, antagonists of inositol-1,4,5-trisphosphate (IP3) receptors. Pretreatment with VU0155056, PLD inhibitor, or BD-1047 and NE-100, Sigma-1R antagonists, reduced the [Ca2+]i response elicited by OXA (17-33). Cocaine potentiated the increase in [Ca2+]i by OXA (17-33); the potentiation was abolished by Sigma-1R antagonists. Our results support an additional signaling mechanism for orexin A-OX1 via choline-Sigma-1R and a critical role for Sigma-1R in the cocaine-orexin A interaction in nucleus accumbens neurons.


Assuntos
Colina/metabolismo , Cocaína/farmacologia , Neurônios/fisiologia , Núcleo Accumbens/fisiologia , Receptores de Orexina/metabolismo , Orexinas/metabolismo , Receptores sigma/metabolismo , Animais , Animais Recém-Nascidos , Regulação da Expressão Gênica , Neurônios/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Receptores de Orexina/genética , Orexinas/genética , Ratos , Ratos Sprague-Dawley , Receptores sigma/genética , Vasoconstritores/farmacologia
10.
Int J Mol Sci ; 22(11)2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34064122

RESUMO

The σ2 receptor (transmembrane protein 97), which is involved in cholesterol homeostasis, is of high relevance for neoplastic processes. The upregulated expression of σ2 receptors in cancer cells and tissue in combination with the antiproliferative potency of σ2 receptor ligands motivates the research in the field of σ2 receptors for the diagnosis and therapy of different types of cancer. Starting from the well described 2-(4-(1H-indol-1-yl)butyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline class of compounds, we synthesized a novel series of fluorinated derivatives bearing the F-atom at the aromatic indole/azaindole subunit. RM273 (2-[4-(6-fluoro-1H-pyrrolo[2,3-b]pyridin-1-yl)butyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline) was selected for labelling with 18F and evaluation regarding detection of σ2 receptors in the brain by positron emission tomography. Initial metabolism and biodistribution studies of [18F]RM273 in healthy mice revealed promising penetration of the radioligand into the brain. Preliminary in vitro autoradiography on brain cryosections of an orthotopic rat glioblastoma model proved the potential of the radioligand to detect the upregulation of σ2 receptors in glioblastoma cells compared to healthy brain tissue. The results indicate that the herein developed σ2 receptor ligand [18F]RM273 has potential to assess by non-invasive molecular imaging the correlation between the availability of σ2 receptors and properties of brain tumors such as tumor proliferation or resistance towards particular therapies.


Assuntos
Encéfalo/metabolismo , Radioisótopos de Flúor/química , Radioisótopos de Flúor/metabolismo , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/metabolismo , Receptores sigma/metabolismo , Animais , Feminino , Humanos , Ligantes , Masculino , Camundongos , Neoplasias/metabolismo , Ratos , Ratos Endogâmicos F344 , Tetra-Hidroisoquinolinas/química , Tetra-Hidroisoquinolinas/metabolismo
11.
Int J Mol Sci ; 22(11)2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34064275

RESUMO

Sigma-1 receptor (chaperone Sigma1R) is an intracellular protein with chaperone functions, which is expressed in various organs, including the brain. Sigma1R participates in the regulation of physiological mechanisms of anxiety (Su, T. P. et al., 2016) and reactions to emotional stress (Hayashi, T., 2015). In 2006, fabomotizole (ethoxy-2-[2-(morpholino)-ethylthio]benzimidazole dihydrochloride) was registered in Russia as an anxiolytic (Seredenin S. and Voronin M., 2009). The molecular targets of fabomotizole are Sigma1R, NRH: quinone reductase 2 (NQO2), and monoamine oxidase A (MAO-A) (Seredenin S. and Voronin M., 2009). The current study aimed to clarify the dependence of fabomotizole anxiolytic action on its interaction with Sigma1R and perform a docking analysis of fabomotizole interaction with Sigma1R. An elevated plus maze (EPM) test revealed that the anxiolytic-like effect of fabomotizole (2.5 mg/kg i.p.) administered to male BALB/c mice 30 min prior EPM exposition was blocked by Sigma1R antagonists BD-1047 (1.0 mg/kg i.p.) and NE-100 (1.0 mg/kg i.p.) pretreatment. Results of initial in silico study showed that fabomotizole locates in the active center of Sigma1R, reproducing the interactions with the site's amino acids common for established Sigma1R ligands, with the ΔGbind value closer to that of agonist (+)-pentazocine in the 6DK1 binding site.


Assuntos
Ansiolíticos/farmacologia , Ansiedade/tratamento farmacológico , Benzimidazóis/farmacologia , Chaperonas Moleculares/metabolismo , Morfolinas/farmacologia , Receptores sigma/metabolismo , Animais , Anisóis/farmacologia , Sítios de Ligação/fisiologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Etilenodiaminas/farmacologia , Ligantes , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Propilaminas/farmacologia , Federação Russa
12.
Psychopharmacology (Berl) ; 238(7): 2043-2044, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34115156

RESUMO

With respect to Guo's inspiring article (Guo et al. 2021), we would like to suggest several corrections about some of the figures. We felt obliged to write this erratum letter as these incompatibilities may cause confusion for the readers.


Assuntos
Transtorno Depressivo Maior/metabolismo , Receptores sigma/metabolismo , Analgésicos Opioides/metabolismo , Analgésicos Opioides/farmacologia , Animais , Ligantes , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Ratos
13.
Biochemistry (Mosc) ; 86(4): 471-479, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33941067

RESUMO

Huntington's disease (HD) is a neurodegenerative, dominantly inherited genetic disease caused by expansion of the polyglutamine tract in the huntingtin gene. At the cellular level, HD is characterized by the accumulation of mutant huntingtin protein in brain cells, resulting in the development of the HD phenotype, which includes mental disorders, decreased cognitive abilities, and progressive motor impairments in the form of chorea. Despite numerous studies, no unambigous connection between the accumulation of mutant protein and selective death of striatal neurons has yet been established. Recent studies have shown impairments in the calcium homeostasis in striatal neurons in HD. These cells are extremely sensitive to changes in the cytoplasmic concentration of calcium and its excessive increase leads to their death. One of the possible ways to normalize the balance of calcium in striatal neurons is through the sigma 1 receptor (S1R), which act as a calcium sensor that also exhibits modulating chaperone activity upon the cell stress observed during the development of many neurodegenerative diseases. The fact that S1R is a ligand-operated protein makes it a new promising molecular target for the development of drug therapy of HD based on the agonists of this receptor.


Assuntos
Cálcio/metabolismo , Corpo Estriado/metabolismo , Doença de Huntington/metabolismo , Neurônios/metabolismo , Receptores sigma/antagonistas & inibidores , Animais , Corpo Estriado/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Humanos , Doença de Huntington/tratamento farmacológico , Neurônios/efeitos dos fármacos , Receptores sigma/metabolismo
14.
Biomed Pharmacother ; 140: 111749, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34058437

RESUMO

Inflammation is a primary defense and immune response. However, under pathological conditions, the inflammation processes always become uncontrolled and lead to chronic diseases. Bufotenine, as a natural component from toad venom, showed great potential for development as a novel anti-inflammation and analgesia agent. This study aimed to investigate the therapeutic effects of bufotenine against inflammation and pain on animal models with a focus on lipid metabolism. In pharmacological studies, bufotenine significantly inhibited the swelling rates on formalin-induced paw edema model, and increased paw withdrawal mechanical thresholds (PWMTs) in von Frey test and thermal pain thresholds (TPTs) in hot-plate test. High-sensitivity lipidomics analysis revealed the effects might be related to the down-regulation of inflammatory mediators from cyclooxygenase (COX), lipoxygenase (LOX), cytochrome P450 (CYP450), linoleic acid (LA), docosahexaenoic acid (DHA) and other pathways. The activities might result from the binding of bufotenine and its receptors, including sigma-1 receptor and 5-Hydroxytryptamine receptor 3A, thus regulating lipid metabolism pathway. The research provided a systemic evidence for the actions and mechanism of bufotenine. It suggested that the natural compound might be a potential candidate for reducing inflammatory pain disorders.


Assuntos
Analgésicos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Bufotenina/uso terapêutico , Edema/tratamento farmacológico , Metabolismo dos Lipídeos/efeitos dos fármacos , Dor/tratamento farmacológico , Analgésicos/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Bufotenina/farmacologia , Ciclo-Oxigenase 2/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Ácidos Docosa-Hexaenoicos/metabolismo , Edema/metabolismo , Feminino , Ácido Linoleico/metabolismo , Lipoxigenase/metabolismo , Masculino , Camundongos Endogâmicos ICR , Simulação de Acoplamento Molecular , Dor/metabolismo , Receptores de Serotonina/metabolismo , Receptores sigma/metabolismo , Transdução de Sinais/efeitos dos fármacos
15.
Int J Mol Sci ; 22(5)2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33803075

RESUMO

Methamphetamine is, worldwide, one of the most consumed drugs of abuse. One important side effect is neurodegeneration leading to a decrease in life expectancy. The aim of this paper was to check whether the drug affects one of the receptors involved in neurodegeneration/neuroprotection events, namely the adenosine A2A receptor (A2AR). First, we noticed that methamphetamine does not affect A2A functionality if the receptor is expressed in a heterologous system. However, A2AR becomes sensitive to the drug upon complexes formation with the cannabinoid CB1 receptor (CB1R) and the sigma 1 receptor (σ1R). Signaling via both adenosine A2AR and cannabinoid CB1R was affected by methamphetamine in cells co-expressing the two receptors. In striatal primary cultures, the A2AR-CB1R heteromer complex was detected and methamphetamine not only altered its expression but completely blocked the A2AR- and the CB1R-mediated activation of the mitogen activated protein kinase (MAPK) pathway. In conclusion, methamphetamine, with the participation of σ1R, alters the expression and function of two interacting receptors, A2AR, which is a therapeutic target for neuroprotection, and CB1R, which is the most abundant G protein-coupled receptor (GPCR) in the brain.


Assuntos
Antagonistas do Receptor A2 de Adenosina/farmacologia , Corpo Estriado/metabolismo , Metanfetamina/farmacologia , Neurônios/metabolismo , Receptor A2A de Adenosina/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Receptores sigma/metabolismo , Animais , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Células HEK293 , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos
16.
Int J Mol Sci ; 22(8)2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33920913

RESUMO

The sigma-1 receptor (S1R) is a 223 amino acid-long transmembrane endoplasmic reticulum (ER) protein. The S1R modulates the activity of multiple effector proteins, but its signaling functions are poorly understood. S1R is associated with cholesterol, and in our recent studies we demonstrated that S1R association with cholesterol induces the formation of S1R clusters. We propose that these S1R-cholesterol interactions enable the formation of cholesterol-enriched microdomains in the ER membrane. We hypothesize that a number of secreted and signaling proteins are recruited and retained in these microdomains. This hypothesis is consistent with the results of an unbiased screen for S1R-interacting partners, which we performed using the engineered ascorbate peroxidase 2 (APEX2) technology. We further propose that S1R agonists enable the disassembly of these cholesterol-enriched microdomains and the release of accumulated proteins such as ion channels, signaling receptors, and trophic factors from the ER. This hypothesis may explain the pleotropic signaling functions of the S1R, consistent with previously observed effects of S1R agonists in various experimental systems.


Assuntos
Colesterol/metabolismo , Doenças Neurodegenerativas/metabolismo , Receptores sigma/metabolismo , Animais , Ontologia Genética , Células HeLa , Humanos , Microdomínios da Membrana/metabolismo , Terapia de Alvo Molecular
17.
Eur J Med Chem ; 219: 113443, 2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-33901806

RESUMO

1,3-Dioxanes 1 and cyclohexanes 2 bearing a phenyl ring and an aminoethyl moiety in 1,3-relationship to each other represent highly potent σ1 receptor antagonists. In order to increase the chemical stability of the acetalic 1,3-dioxanes 1 and the polarity of the cyclohexanes 2, tetrahydropyran derivatives 3 equipped with the same substituents were designed, synthesized and pharmacologically evaluated. The key step of the synthesis was a lipase-catalyzed enantioselective acetylation of the alcohol (R)-5 leading finally to enantiomerically pure test compounds 3a-g. With respect to σ1 receptor affinity and selectivity over a broad range of related (σ2, PCP binding site) and further targets, the enantiomeric benzylamines 3a and cyclohexylmethylamines 3b represent the most promising drug candidates of this series. However, the eudismic ratio for σ1 binding is only in the range of 2.5-3.3. Classical molecular dynamics (MD) simulations confirmed the same binding pose for both the tetrahydropyran 3 and cyclohexane derivatives 2 at the σ1 receptor, according to which: i) the protonated amino moiety of (2S,6R)-3a engages the same key polar interactions with Glu172 (ionic) and Phe107 (π-cation), ii) the lipophilic parts of (2S,6R)-3a are hosted in three hydrophobic regions of the σ1 receptor, and iii) the O-atom of the tetrahydropyran derivatives 3 does not show a relevant interaction with the σ1 receptor. Further in silico evidences obtained by the application of free energy perturbation and steered MD techniques fully supported the experimentally observed difference in receptor/ligand affinities. Tetrahydropyrans 3 require a lower dissociative force peak than cyclohexane analogs 2. Enantiomeric benzylamines 3a and cyclohexylmethylamines 3b were able to inhibit the growth of the androgen negative human prostate cancer cell line DU145. The cyclohexylmethylamine (2S,6R)-3b showed the highest σ1 affinity (Ki(σ1) = 0.95 nM) and the highest analgesic activity in vivo (67%).


Assuntos
Analgésicos/síntese química , Antineoplásicos/síntese química , Piranos/química , Receptores sigma/metabolismo , Analgésicos/metabolismo , Analgésicos/uso terapêutico , Animais , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Humanos , Hiperalgesia/tratamento farmacológico , Ligantes , Camundongos , Simulação de Dinâmica Molecular , Ligação Proteica , Piranos/metabolismo , Receptores sigma/química , Estereoisomerismo , Relação Estrutura-Atividade , Termodinâmica
18.
Dokl Biochem Biophys ; 497(1): 63-65, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33895918

RESUMO

In vitro experiments performed on an isolated human endothelial HUVEC cell culture showed that the anxiolytic fabomotizole, which, in addition to the anxiolytic effect, has neuroprotective and cardioprotective activities largely associated with its agonistic action on sigma-1 receptors and shows a pronounced angiogenic activity. Fabomotizole angiogenic activity is realized in the range concentration from 10-5 to 10-8 M and is doze-dependent. In the literature, data on the presence of angiogenic activity in sigma receptor agonists have not been previously reported.


Assuntos
Ansiolíticos/farmacologia , Benzimidazóis/farmacologia , Morfolinas/farmacologia , Movimento Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Receptores sigma/metabolismo
19.
J Med Chem ; 64(8): 5157-5170, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33826322

RESUMO

The synthesis and pharmacological activity of a new series of 5a,7,8,8a-tetrahydro-4H,6H-pyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine derivatives as potent sigma-1 receptor (σ1R) ligands are reported. A lead optimization program aimed at improving the aqueous solubility of parent racemic nonpolar derivatives led to the identification of several σ1R antagonists with a good absorption, distribution, metabolism, and excretion in vitro profile, no off-target affinities, and characterized by a low basic pKa (around 5) that correlates with high exposure levels in rodents. Two compounds displaying a differential brain-to-plasma ratio distribution profile, 12lR and 12qS, exhibited a good analgesic profile and were selected as preclinical candidates for the treatment of pain.


Assuntos
Analgésicos/química , Receptores sigma/antagonistas & inibidores , Triazóis/química , Analgésicos/metabolismo , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Permeabilidade da Membrana Celular/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Meia-Vida , Humanos , Ligantes , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Dor/tratamento farmacológico , Ratos , Ratos Wistar , Receptores sigma/metabolismo , Relação Estrutura-Atividade , Triazóis/metabolismo , Triazóis/farmacologia , Triazóis/uso terapêutico
20.
Pharmacol Biochem Behav ; 203: 173154, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33609599

RESUMO

Interest in developing NMDA receptor antagonists with reduced side-effects for neurological and psychiatric disorders has been re-energized by the recent introduction of esketamine into clinical practice for treatment-resistant depression. Structural analogs of dextromethorphan bind with low affinity to the NMDA receptor ion channel, have functional effects in vivo, and generally display a lower propensity for side-effects than that of ketamine and other higher affinity antagonists. As such, the aim of the present study was to determine whether a series of N-substituted-3-alkoxy-substituted dextromethorphan analogs produce their anticonvulsant effects through NMDA receptor blockade. Compounds were studied against NMDA-induced seizures in rats. Compounds were administered intracerebroventricularly in order to mitigate confounds of drug metabolism that arise from systemic administration. Comparison of the anticonvulsant potencies to their affinities for NMDA, σ1, and σ2 binding sites were made in order to evaluate the contribution of these receptors to anticonvulsant efficacy. The potencies to block convulsions were positively associated with their affinities to bind to the NMDA receptor ion channel ([3H]-TCP binding) (r = 0.71, p < 0.05) but not to σ1 receptors ([3H]-SKF 10047 binding) (r = -0.31, p = 0.46) or to σ2 receptors ([3H]-DTG binding) (p = -0.38, p = 0.36). This is the first report demonstrating that these dextromethorphan analogs are functional NMDA receptor antagonists in vivo. Given their potential therapeutic utility and favorable side-effect profiles, such low affinity NMDA receptor antagonists could be considered for further development in neurological (e.g., anticonvulsant) and psychiatric (e.g., antidepressant) disorders.


Assuntos
Anticonvulsivantes/administração & dosagem , Dextrometorfano/análogos & derivados , Dextrometorfano/administração & dosagem , Dextrorfano/administração & dosagem , Agonistas de Aminoácidos Excitatórios/efeitos adversos , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , N-Metilaspartato/efeitos adversos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Álcoois/química , Animais , Anticonvulsivantes/metabolismo , Sítios de Ligação , Dextrometorfano/metabolismo , Dextrorfano/metabolismo , Modelos Animais de Doenças , Antagonistas de Aminoácidos Excitatórios/metabolismo , Infusões Intraventriculares , Ligantes , Masculino , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores sigma/metabolismo , Resultado do Tratamento
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