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1.
J Immunol Res ; 2021: 4414544, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34616852

RESUMO

COVID-19 is a respiratory infection caused by the SARS-CoV-2 virus that can rapidly escalate to life-threatening pneumonia and acute respiratory distress syndrome (ARDS). Recently, extracellular high mobility group box 1 (HMGB1) has been identified as an essential component of cytokine storms that occur with COVID-19; HMGB1 levels correlate significantly with disease severity. Thus, the modulation of HMGB1 release may be vital for treating COVID-19. HMGB1 is a ubiquitous nuclear DNA-binding protein whose biological function depends on posttranslational modifications, its redox state, and its cellular localization. The acetylation of HMGB1 is a prerequisite for its translocation from the nucleus to the cytoplasm and then to the extracellular milieu. When released, HMGB1 acts as a proinflammatory cytokine that binds primarily to toll-like receptor 4 (TLR4) and RAGE, thereby stimulating immune cells, endothelial cells, and airway epithelial cells to produce cytokines, chemokines, and other inflammatory mediators. In this study, we demonstrate that inhaled [D-Ala2]-dynorphin 1-6 (leytragin), a peptide agonist of δ-opioid receptors, significantly inhibits HMGB1 secretion in mice with lipopolysaccharide- (LPS-) induced acute lung injury. The mechanism of action involves preventing HMGB1's hyperacetylation at critical lysine residues within nuclear localization sites, as well as promoting the expression of sirtuin 1 (SIRT1), an enzyme known to deacetylate HMGB1. Leytragin's effects are mediated by opioid receptors, since naloxone, an antagonist of opioid receptors, abrogates the leytragin effect on SIRT1 expression. Overall, our results identify leytragin as a promising therapeutic agent for the treatment of pulmonary inflammation associated with HMGB1 release. In a broader context, we demonstrate that the opioidergic system in the lungs may represent a promising target for the treatment of inflammatory lung diseases.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Dinorfinas/farmacologia , Proteína HMGB1/metabolismo , Acetilação , Lesão Pulmonar Aguda/metabolismo , Animais , COVID-19/tratamento farmacológico , COVID-19/metabolismo , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , Receptores Opioides/metabolismo , Sirtuína 1/metabolismo
2.
Int J Mol Sci ; 22(16)2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34445072

RESUMO

Opioid peptides exhibit a wide-ranging tissue distribution and control multiple tissue functions not only through reflex mechanisms involving the central nervous system or the modulation of neurotransmitter release, but also by acting directly at the cellular level by targeting selected receptor subtypes (µ, δ, and κ are among the most frequently expressed) [...].


Assuntos
Peptídeos Opioides/metabolismo , Receptores Opioides/metabolismo , Animais , Encéfalo/metabolismo , Sistema Nervoso Central/metabolismo , Humanos , Transdução de Sinais
3.
Int J Mol Sci ; 22(14)2021 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-34299276

RESUMO

1-cyclohexyl-x-methoxybenzene is a novel psychoactive substance (NPS), first discovered in Europe in 2012 as unknown racemic mixture of its three stereoisomers: ortho, meta and para. Each of these has structural similarities with the analgesic tramadol and the dissociative anesthetic phencyclidine. In light of these structural analogies, and based on the fact that both tramadol and phencyclidine are substances that cause toxic effects in humans, the aim of this study was to investigate the in vitro and in vivo pharmacodynamic profile of these molecules, and to compare them with those caused by tramadol and phencyclidine. In vitro studies demonstrated that tramadol, ortho, meta and para were inactive at mu, kappa and delta opioid receptors. Systemic administration of the three stereoisomers impairs sensorimotor responses, modulates spontaneous motor activity, induces modest analgesia, and alters thermoregulation and cardiorespiratory responses in the mouse in some cases, with a similar profile to that of tramadol and phencyclidine. Naloxone partially prevents only the visual sensorimotor impairments caused by three stereoisomers, without preventing other effects. The present data show that 1-cyclohexyl-x-methoxybenzene derivatives cause pharmaco-toxicological effects by activating both opioid and non-opioid mechanisms and suggest that their use could potentially lead to abuse and bodily harm.


Assuntos
Analgésicos Opioides/toxicidade , Anisóis/toxicidade , Derivados de Benzeno/toxicidade , Alucinógenos/toxicidade , Fenciclidina/toxicidade , Psicotrópicos/toxicidade , Receptores Opioides/metabolismo , Tramadol/toxicidade , Analgésicos Opioides/química , Animais , Anisóis/química , Derivados de Benzeno/química , Células Cultivadas , Cricetinae , Alucinógenos/química , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos ICR , Modelos Animais , Fenciclidina/química , Psicotrópicos/química , Tramadol/química
4.
Molecules ; 26(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199486

RESUMO

In this study, we aimed to design and synthesize novel molecules carrying both the thiazole and piperazine rings in their structures and to investigate their antinociceptive activity. Targeted compounds were obtained by reacting thiosemicarbazide derivative and appropriate 2-bromoacetophenone in ethanol. The structures of the obtained compounds were determined using data from various spectroscopic methods (IR, 1H-NMR, 13C-NMR, and LCMSMS). Experimental data from in vivo tests showed that test compounds 3a-3c, 3f, and 3g (50 mg/kg) significantly prolonged reaction times of animals in tail-clip and hot-plate tests compared to the controls, indicating that these compounds possess centrally mediated antinociceptive activities. Furthermore, these compounds reduced the number of writhing behaviors in the acetic acid-induced writhing tests, showing that the compounds also possess peripheral antinociceptive activity. In the mechanistic studies, naloxone pre-treatments abolished the antinociceptive activities of compounds 3a-3c, 3f, and 3g, indicating that opioidergic mechanisms were involved in their antinociceptive effects. Molecular docking studies demonstrating significant interactions between the active compounds and µ- and δ-opioid receptor proteins supported the pharmacological findings. This study is the first showing that molecules designed to bear thiazole and piperazine moieties together on their structure exert centrally and peripherally mediated antinociceptive effects by activating the opioid system.


Assuntos
Acetofenonas/química , Analgésicos/administração & dosagem , Analgésicos/síntese química , Dor/tratamento farmacológico , Receptores Opioides/metabolismo , Semicarbazidas/química , Analgésicos/química , Analgésicos/farmacologia , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Naloxona/administração & dosagem , Naloxona/farmacologia , Dor/metabolismo , Conformação Proteica , Receptores Opioides/química , Receptores Opioides delta/química , Receptores Opioides delta/metabolismo , Receptores Opioides mu/química , Receptores Opioides mu/metabolismo
5.
Molecules ; 26(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34201982

RESUMO

During the last three decades, a variety of different studies on bioactive peptides that are opioid receptor ligands, have been carried out, with regard to their isolation and identification, as well as their molecular functions in living organisms. Thus, in this review, we would like to summarize the present state-of-the art concerning hemorphins, methodological aspects of their identification, and their potential role as therapeutic agents. We have collected and discussed articles describing hemorphins, from their discovery up until now, thus presenting a very wide spectrum of their characteristic and applications. One of the major assets of the present paper is a combination of analytical and pharmacological aspects of peptides described by a team who participated in the initial research on hemorphins. This review is, in part, focused on the analysis of endogenous opioid peptides in biological samples using advanced techniques, description of the identification of synthetic/endogenous hemorphins, their involvement in pharmacology, learning, pain and other function. Finally, the part regarding hemorphin analogues and their synthesis, has been added.


Assuntos
Peptídeos Opioides/metabolismo , Dor/metabolismo , Fragmentos de Peptídeos/metabolismo , Receptores Opioides/metabolismo , Animais , Humanos
6.
Int J Mol Sci ; 22(14)2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34299013

RESUMO

Mucosal CD4+ T lymphocytes display a potent opioid-mediated analgesic activity in interleukin (IL)-10 knockout mouse model of inflammatory bowel diseases (IBD). Considering that endogenous opioids may also exhibit anti-inflammatory activities in the periphery, we examined the consequences of a peripheral opioid receptor blockade by naloxone-methiodide, a general opioid receptor antagonist unable to cross the blood-brain barrier, on the development of piroxicam-accelerated colitis in IL-10-deficient (IL-10-/-) mice. Here, we show that IL-10-deficient mice treated with piroxicam exhibited significant alterations of the intestinal barrier function, including permeability, inflammation-related bioactive lipid mediators, and mucosal CD4+ T lymphocyte subsets. Opioid receptor antagonization in the periphery had virtually no effect on colitis severity but significantly worsened epithelial cell apoptosis and intestinal permeability. Thus, although the endogenous opioid tone is not sufficient to reduce the severity of colitis significantly, it substantially contributes to the protection of the physical integrity of the epithelial barrier.


Assuntos
Colite/metabolismo , Interleucina-10/genética , Mucosa Intestinal/efeitos dos fármacos , Naloxona/análogos & derivados , Antagonistas de Entorpecentes/administração & dosagem , Piroxicam/farmacologia , Receptores Opioides/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Linfócitos T CD4-Positivos/efeitos dos fármacos , Colite/induzido quimicamente , Colite/genética , Colite/patologia , Citocinas/genética , Citocinas/metabolismo , Células Epiteliais/efeitos dos fármacos , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Interleucina-10/metabolismo , Mucosa Intestinal/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Naloxona/farmacologia , Permeabilidade/efeitos dos fármacos , Compostos de Amônio Quaternário/farmacologia , Índice de Gravidade de Doença
7.
J Med Chem ; 64(10): 6523-6548, 2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-33956427

RESUMO

Because of the problems associated with opioids, drug discovery efforts have been employed to develop opioids with reduced side effects using approaches such as biased opioid agonism, multifunctional opioids, and allosteric modulation of opioid receptors. Receptor targets such as adrenergic, cannabinoid, P2X3 and P2X7, NMDA, serotonin, and sigma, as well as ion channels like the voltage-gated sodium channels Nav1.7 and Nav1.8 have been targeted to develop novel analgesics. Several enzymes, such as soluble epoxide hydrolase, sepiapterin reductase, and MAGL/FAAH, have also been targeted to develop novel analgesics. In this review, old and recent targets involved in pain signaling and compounds acting at these targets are summarized. In addition, strategies employed to reduce side effects, increase potency, and efficacy of opioids are also elaborated. This review should aid in propelling drug discovery efforts to discover novel analgesics.


Assuntos
Analgésicos/química , Descoberta de Drogas , Receptores Opioides/química , Agonistas Adrenérgicos/uso terapêutico , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Epóxido Hidrolases/antagonistas & inibidores , Epóxido Hidrolases/metabolismo , Humanos , Dor/tratamento farmacológico , Receptores Opioides/agonistas , Receptores Opioides/metabolismo , Transdução de Sinais/efeitos dos fármacos , Canais de Sódio Disparados por Voltagem/química , Canais de Sódio Disparados por Voltagem/metabolismo
8.
J Med Chem ; 64(10): 6656-6669, 2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-33998786

RESUMO

The nociceptin/orphanin FQ (N/OFQ)/N/OFQ receptor (NOP) system controls different biological functions including pain and cough reflex. Mixed NOP/opioid receptor agonists elicit similar effects to strong opioids but with reduced side effects. In this work, 31 peptides with the general sequence [Tyr/Dmt1,Xaa5]N/OFQ(1-13)-NH2 were synthesized and pharmacologically characterized for their action at human recombinant NOP/opioid receptors. The best results in terms of NOP versus mu opioid receptor potency were obtained by substituting both Tyr1 and Thr5 at the N-terminal portion of N/OFQ(1-13)-NH2 with the noncanonical amino acid Dmt. [Dmt1,5]N/OFQ(1-13)-NH2 has been identified as the most potent dual NOP/mu receptor peptide agonist so far described. Experimental data have been complemented by in silico studies to shed light on the molecular mechanisms by which the peptide binds the active form of the mu receptor. Finally, the compound exerted antitussive effects in an in vivo model of cough.


Assuntos
Peptídeos/química , Receptores Opioides mu/agonistas , Receptores Opioides/agonistas , Animais , Sítios de Ligação , Tosse/induzido quimicamente , Tosse/tratamento farmacológico , Modelos Animais de Doenças , Cobaias , Humanos , Interações Hidrofóbicas e Hidrofílicas , Masculino , Simulação de Dinâmica Molecular , Peptídeos/metabolismo , Peptídeos/uso terapêutico , Receptores Opioides/metabolismo , Receptores Opioides mu/genética , Receptores Opioides mu/metabolismo , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Proteínas Recombinantes/isolamento & purificação , Relação Estrutura-Atividade
9.
J Med Chem ; 64(11): 7555-7564, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34008968

RESUMO

RFamide-related peptide-3 (RFRP-3) and neuropeptide FF (NPFF) target two different receptor subtypes called neuropeptide FF1 (NPFF1R) and neuropeptide FF2 (NPFF2R) that modulate several functions. However, the study of their respective role is severely limited by the absence of selective blockers. We describe here the design of a highly selective NPFF1R antagonist called RF3286, which potently blocks RFRP-3-induced hyperalgesia in mice and luteinizing hormone release in hamsters. We then showed that the pharmacological blockade of NPFF1R in mice prevents the development of fentanyl-induced hyperalgesia while preserving its analgesic effect. Altogether, our data indicate that RF3286 represents a useful pharmacological tool to study the involvement of the NPFF1R/RFRP-3 system in different functions and different species. Thanks to this compound, we showed that this system is critically involved in the development of opioid-induced hyperalgesia, suggesting that NPFF1R antagonists might represent promising therapeutic tools to improve the use of opioids in the treatment of chronic pain.


Assuntos
Analgésicos Opioides/efeitos adversos , Dipeptídeos/química , Receptores de Neuropeptídeos/antagonistas & inibidores , Animais , Cricetinae , Dipeptídeos/metabolismo , Dipeptídeos/farmacologia , Dipeptídeos/uso terapêutico , Feminino , Fentanila/efeitos adversos , Meia-Vida , Humanos , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Hormônio Luteinizante/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neuropeptídeos/química , Neuropeptídeos/metabolismo , Neuropeptídeos/farmacologia , Neuropeptídeos/uso terapêutico , Isoformas de Proteínas/química , Isoformas de Proteínas/metabolismo , Receptores de Neuropeptídeos/metabolismo , Receptores Opioides/química , Receptores Opioides/metabolismo , Relação Estrutura-Atividade
10.
Chem Biodivers ; 18(6): e2100125, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33893724

RESUMO

Previous studies have characterized a saline extract from Microgramma vacciniifolia rhizome and its lectin (MvRL)-rich fraction with low acute toxicity. In the present study, we evaluated these preparations for acute toxicity (1,000 mg/kg) and antinociceptive and anti-inflammatory activities (100-400 mg/kg for the extract and 25-50 mg/kg for the fraction). No signs of toxicity were observed. Both the extract and fraction increased the latency period for nociception in the hot plate assay, decreased writhing induced by acetic acid, and promoted analgesic effects in phases 1 and 2 of the formalin test. The antinociceptive mechanism was attributed to interactions with opioid receptors and K+ ATPase channels. The extract and fraction decreased carrageenan-induced paw edema in 46.15 % and 77.22 %, respectively, at the highest doses evaluated. Furthermore, the fraction was shown to act on the bradykinin pathway. The ability to decrease leukocyte migration after treatment was also verified in the peritonitis and air pouch models. In exudates collected from air pouches, decreased tumor necrosis factor (TNF)-α and increased interleukin (IL)-10 levels were noted. Both the extract and fraction also effectively inhibited the development of granulomatous tissue. In conclusion, the substances investigated in this study can be used for the development of novel therapeutic options for pain and inflammatory processes.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Edema/tratamento farmacológico , Lectinas/química , Extratos Vegetais/farmacologia , Rizoma/química , Analgésicos/química , Analgésicos/isolamento & purificação , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Carragenina , Movimento Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Leucócitos/efeitos dos fármacos , Camundongos , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Receptores Opioides/metabolismo , Salinidade , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores , ATPase Trocadora de Sódio-Potássio/metabolismo
11.
Scand J Immunol ; 94(2): e13041, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33817820

RESUMO

This review discusses the accumulated evidence that pro-opiomelanocortin (POMC) gene products as well as other pituitary neuropeptides derived from related genes (Proenkephalin, PENK; Prodynorphin, PDYN, and Pronociceptin, PNOC) can exert direct effects on B lymphocytes to modulate their functions. We also review the available data on receptor systems that might be involved in the transmission of such hormonal signals to B cells.


Assuntos
Linfócitos B/metabolismo , Neuropeptídeos/metabolismo , Animais , Encefalinas/metabolismo , Humanos , Pró-Opiomelanocortina/metabolismo , Precursores de Proteínas/metabolismo , Receptores Opioides/metabolismo
12.
Am J Physiol Gastrointest Liver Physiol ; 320(6): G1093-G1104, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33908261

RESUMO

Constipation and abdominal pain are commonly encountered in opioid-induced bowel dysfunction (OBD). The underlying mechanisms are incompletely understood, and treatments are not satisfactory. As patients with OBD often have fecal retention, we aimed to determine whether fecal retention plays a pathogenic role in the development of constipation and abdominal pain in OBD, and if so to investigate the mechanisms. A rodent model of OBD was established by daily morphine treatment at 10 mg/kg for 7 days. Bowel movements, colonic muscle contractility, visceromotor response to colorectal distention, and cell excitability of colon-projecting dorsal root ganglion neurons were determined in rats fed with normal pellet food, or with clear liquid diet. Morphine treatment (Mor) reduced fecal outputs starting on day 1, and caused fecal retention afterward. Compared with controls, Mor rats demonstrated suppressed muscle contractility, increased neuronal excitability, and visceral hypersensitivity. Expression of cyclooxygenase-2 (COX-2) and nerve growth factor (NGF) was upregulated in the smooth muscle of the distended colon in Mor rats. However, prevention of fecal retention by feeding rats with clear liquid diet blocked upregulation of COX-2 and NGF, restored muscle contractility, and attenuated visceral hypersensitivity in Mor rats. Moreover, inhibition of COX-2 improved smooth muscle function and fecal outputs, whereas anti-NGF antibody administration attenuated visceral hypersensitivity in Mor rats. Morphine-induced fecal retention is an independent pathogenic factor for motility dysfunction and visceral hypersensitivity in rats with OBD. Liquid diet may have therapeutic potential for OBD by preventing fecal retention-induced mechanotranscription of COX-2 and NGF.NEW & NOTEWORTHY Our preclinical study shows that fecal retention is a pathogenic factor in opioid-induced bowel dysfunction, as prevention of fecal retention with liquid diet improved motility and attenuated visceral hyperalgesia in morphine-treated animals by blocking expression of cyclooxygenase-2 and nerve growth factor in the colon.


Assuntos
Motilidade Gastrointestinal/fisiologia , Hiperalgesia/fisiopatologia , Morfina/farmacologia , Constipação Induzida por Opioides/fisiopatologia , Animais , Ciclo-Oxigenase 2/metabolismo , Motilidade Gastrointestinal/efeitos dos fármacos , Humanos , Hiperalgesia/metabolismo , Masculino , Fator de Crescimento Neural/metabolismo , Constipação Induzida por Opioides/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Opioides/metabolismo , Células Receptoras Sensoriais/efeitos dos fármacos , Células Receptoras Sensoriais/metabolismo
13.
Front Immunol ; 12: 647209, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33841428

RESUMO

Background: Cholangiocarcinoma was a highly malignant liver cancer with poor prognosis, and immune infiltration status was considered an important factor in response to immunotherapy. In this investigation, we tried to locate immune infiltration related genes of cholangiocarcinoma through combination of bulk-sequencing and single-cell sequencing technology. Methods: Single sample gene set enrichment analysis was used to annotate immune infiltration status in datasets of TCGA CHOL, GSE32225, and GSE26566. Differentially expressed genes between high- and low-infiltrated groups in TCGA dataset were yielded and further compressed in other two datasets through backward stepwise regression in R environment. Single-cell sequencing data of GSE138709 was loaded by Seurat software and was used to examined the expression of infiltration-related gene set. Pathway changes in malignant cell populations were analyzed through scTPA web tool. Results: There were 43 genes differentially expressed between high- and low-immune infiltrated patients, and after further compression, PNOC and LAIR2 were significantly correlated with high immune infiltration status in cholangiocarcinoma. Through analysis of single-cell sequencing data, PNOC was mainly expressed by infiltrated B cells in tumor microenvironment, while LAIR2 was expressed by Treg cells and partial GZMB+ CD8 T cells, which were survival related and increased in tumor tissues. High B cell infiltration levels were related to better overall survival. Also, malignant cell populations demonstrated functionally different roles in tumor progression. Conclusion: PNOC and LAIR2 were biomarkers for immune infiltration evaluation in cholangiocarcinoma. PNOC, expressed by B cells, could predict better survival of patients, while LAIR2 was a potential marker for exhaustive T cell populations, correlating with worse survival of patients.


Assuntos
Linfócitos B/metabolismo , Neoplasias dos Ductos Biliares/genética , Biomarcadores Tumorais/genética , Colangiocarcinoma/genética , Precursores de Proteínas/genética , Receptores Imunológicos/genética , Receptores Opioides/genética , Linfócitos T/metabolismo , Microambiente Tumoral/genética , Linfócitos B/imunologia , Neoplasias dos Ductos Biliares/metabolismo , Biomarcadores Tumorais/metabolismo , Colangiocarcinoma/metabolismo , Bases de Dados Genéticas , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Prognóstico , Precursores de Proteínas/metabolismo , Receptores Imunológicos/metabolismo , Receptores Opioides/metabolismo , Análise de Sequência de DNA/métodos , Análise de Célula Única/métodos , Análise de Sobrevida , Linfócitos T/imunologia , Microambiente Tumoral/imunologia
14.
Molecules ; 26(6)2021 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-33799356

RESUMO

The process of modern drug design would not exist in the current form without computational methods. They are part of every stage of the drug design pipeline, supporting the search and optimization of new bioactive substances. Nevertheless, despite the great help that is offered by in silico strategies, the power of computational methods strongly depends on the input data supplied at the stage of the predictive model construction. The studies on the efficiency of the computational protocols most often focus on global efficiency. They use general parameters that refer to the whole dataset, such as accuracy, precision, mean squared error, etc. In the study, we examined machine learning predictions obtained for opioid receptors (mu, kappa, delta) and focused on cases for which the predictions were the most accurate and the least accurate. Moreover, by using docking, we tried to explain prediction errors. We attempted to develop a rule of thumb, which can help in the prediction of compound activity towards opioid receptors via docking, especially those that have been incorrectly predicted by machine learning. We found out that although the combination of ligand- and structure-based path can be beneficial for the prediction accuracy, there still remain cases that cannot be reliably predicted by any available modeling method. In addition to challenging ligand- and structure-based predictions, we also examined the role of the application of machine-learning methods in comparison to simple statistical methods for both standard ligand-based representations (molecular fingerprints) and interaction fingerprints. All approaches were confronted in both classification (where compounds were assigned to the group of active and inactive group constructed on the basis of Ki values) and regression (where exact Ki value was predicted) experiments.


Assuntos
Receptores Opioides/metabolismo , Desenho de Fármacos , Ligantes , Aprendizado de Máquina , Simulação de Acoplamento Molecular/métodos
15.
Pharmacol Biochem Behav ; 204: 173157, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33647274

RESUMO

Opioid receptors modulate neurochemical and behavioral responses to drugs of abuse in nonclinical models. Samidorphan (SAM) is a new molecular entity that binds with high affinity to human mu- (µ), kappa- (κ), and delta- (δ) opioid receptors and functions as a µ-opioid receptor antagonist with partial agonist activity at κ- and δ-opioid receptors. Based on its in vitro profile, we hypothesized that SAM would block key neurobiological effects of drugs of abuse. Therefore, we assessed the effects of SAM on ethanol-, oxycodone-, cocaine-, and amphetamine-induced increases in extracellular dopamine (DAext) in the nucleus accumbens shell (NAc-sh), and ethanol and cocaine self-administration behavior in rats. In microdialysis studies, administration of SAM alone did not result in measurable changes in NAc-sh DAext when given across a large range of doses. However, SAM markedly decreased average and maximal increases in NAc-sh DAext produced by each of the drugs of abuse tested. In behavioral studies, SAM attenuated fixed-ratio ethanol self-administration and progressive ratio cocaine self-administration. These results highlight the potential of SAM to counteract the neurobiological and behavioral effects of several drugs of abuse with differing mechanisms of action.


Assuntos
Dopamina/metabolismo , Naltrexona/análogos & derivados , Antagonistas de Entorpecentes/farmacologia , Receptores Opioides/metabolismo , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Anfetamina/farmacologia , Animais , Cocaína/farmacologia , Etanol/farmacologia , Humanos , Masculino , Microdiálise/métodos , Naltrexona/farmacologia , Núcleo Accumbens/metabolismo , Oxicodona/farmacologia , Ratos , Ratos Wistar , Receptores Opioides mu/metabolismo , Autoadministração/métodos
16.
Int J Mol Sci ; 22(5)2021 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-33671048

RESUMO

Previous studies have shown that genetically selected Marchigian Sardinian alcohol-preferring (msP) rats consume excessive amounts of ethanol to self-medicate from negative moods and to relieve innate hypersensitivity to stress. This phenotype resembling a subset of alcohol use disorder (AUD) patients, appears to be linked to a dysregulation of the equilibrium between stress and antistress mechanisms in the extended amygdala. Here, comparing water and alcohol exposed msP and Wistar rats we evaluate the transcript expression of the anti-stress opioid-like peptide nociceptin/orphanin FQ (N/OFQ) and its receptor NOP as well as of dynorphin (DYN) and its cognate κ-opioid receptor (KOP). In addition, we measured the transcript levels of corticotropin-releasing factor (CRF), CRF receptor 1 (CRF1R), brain-derived neurotrophic factor (BDNF) and of the tropomyosin receptor kinase B receptor (Trk-B). Results showed an innately up-regulation of the CRFergic system, mediating negative mood and stress responses, as well as an inherent up-regulation of the anti-stress N/OFQ system, both in the amygdala (AMY) and bed nucleus of the stria terminalis (BNST) of msP rats. The up-regulation of this latter system may reflect an attempt to buffer the negative condition elicited by the hyperactivity of pro-stress mechanisms since results showed that voluntary alcohol consumption dampened N/OFQ. Alcohol exposure also reduced the expression of dynorphin and CRF transmissions in the AMY of msP rats. In the BNST, alcohol intake led to a more complex reorganization of these systems increasing receptor transcripts in msP rats, along with an increase of CRF and a decrease of N/OFQ transcripts, respectively. Moreover, mimicking the effects of alcohol in the AMY we observed that the activation of NOP receptor by intracerebroventricular administration of N/OFQ in msP rats caused an increase of BDNF and a decrease of CRF transcripts. Our study indicates that both stress and anti-stress mechanisms are dysregulated in the extended AMY of msP rats. The voluntary alcohol drinking, as well as NOP agonism, have a significant impact on neuropeptidergic systems arrangement, bringing the systems back to normalization.


Assuntos
Consumo de Bebidas Alcoólicas/fisiopatologia , Alcoolismo/patologia , Tonsila do Cerebelo/patologia , Dinorfinas/farmacologia , Etanol/toxicidade , Peptídeos Opioides/farmacologia , Fragmentos de Peptídeos/farmacologia , Receptores Opioides/metabolismo , Alcoolismo/etiologia , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Animais , Comportamento Animal , Masculino , Neurotransmissores/farmacologia , Ratos , Ratos Wistar , Receptores Opioides/genética
17.
Bioorg Chem ; 109: 104702, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33631465

RESUMO

In the present study, the role of 3-hydroxy group of a series of epoxymorphinan derivatives in their binding affinity and selectivity profiles toward the opioid receptors (ORs) has been investigated. It was found that the 3-hydroxy group was crucial for the binding affinity of these derivatives for all three ORs due to the fact that all the analogues 1a-e exhibited significantly higher binding affinities compared to their counterpart 3-dehydroxy ones 6a-e. Meanwhile most compounds carrying the 3-hydroxy group possessed similar selectivity profiles for the kappa opioid receptor over the mu opioid receptor as their corresponding 3-dehydroxy derivatives. [35S]-GTPγS functional assay results indicated that the 3-hydroxy group of these epoxymorphinan derivatives was important for maintaining their potency on the ORs with various effects. Further molecular modeling studies helped comprehend the remarkably different binding affinity and functional profiles between compound 1c (NCP) and its 3-dehydroxy analogue 6c.


Assuntos
Morfinanos/química , Morfinanos/farmacologia , Receptores Opioides/metabolismo , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Receptores Opioides/química
18.
Eur J Pharmacol ; 896: 173900, 2021 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-33545158

RESUMO

Tissue injury results in the release of inflammatory mediators, including a cascade of nociceptive substances, which contribute to development of hyperalgesia. In addition, during this process endogenous analgesic substances are also peripherally released with the aim of controlling the hyperalgesia. Thus, the present study aimed to investigate whether inflammatory mediators TNF-α, IL-1ß, CXCL1, norepinephrine (NE) and prostaglandin E2 (PGE2) may be involved in the deflagration of peripheral endogenous modulation of inflammatory pain by activation of the opioid system. Thus, male Swiss mice and the paw withdrawal test were used. All substances were injected by the intraplantar route. Carrageenan, TNF-α, CXCL-1, IL1-ß, NE and PGE2 induced hyperalgesia. Selectives µ (clocinamox), δ (naltrindole) and κ (norbinaltorphimine, nor-BNI) and non-selective (naloxone) opioid receptor antagonists potentiated the hyperalgesia induced by carrageenan, TNF-α, CXCL-1 and IL1-ß. In contrast, when the enzyme N-aminopeptidase involved in the degradation of endogenous opioid peptides was inhibited by bestatin, the hyperalgesia was significantly reduced. In addition, the western blotting assay indicated that the expression of the opioid δ receptor was increased after intraplantar injection of carrageenan. The data obtained in this work corroborate the hypothesis that TNF-α, CXCL-1 and IL-ß cause, in addition to hyperalgesia, the release of endogenous substances such as opioid peptides, which in turn exert endogenous control over peripheral inflammatory pain.


Assuntos
Quimiocina CXCL1 , Hiperalgesia/induzido quimicamente , Interleucina-1beta , Nociceptividade , Dor Nociceptiva/induzido quimicamente , Peptídeos Opioides/metabolismo , Receptores Opioides/metabolismo , Fator de Necrose Tumoral alfa , Animais , Carragenina , Dinoprostona , Modelos Animais de Doenças , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatologia , Hiperalgesia/prevenção & controle , Masculino , Camundongos , Antagonistas de Entorpecentes/farmacologia , Nociceptividade/efeitos dos fármacos , Dor Nociceptiva/metabolismo , Dor Nociceptiva/fisiopatologia , Dor Nociceptiva/prevenção & controle , Norepinefrina , Receptores Opioides/efeitos dos fármacos , Transdução de Sinais
19.
J Ethnopharmacol ; 270: 113872, 2021 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-33485984

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Mu opioid receptor (MOR) is mainly a drug target for analgesia. Opioid-like agonists such as morphine have been clinically used for analgesia but have potential adverse effects. MOR antagonists have been demonstrated to alleviate these side effects. Plants (Carthamus tinctorius L, Cynanchum otophyllum C. K. Schneid., Coffea arabica L., Prinsepia utilis Royle and Lepidium meyenii Walp.) and Ganoderma fungi (Ganoderma hainanense J. D. Zhao, Ganoderma capense (Lloyd) Teng, Ganoderma cochlear (Blume et Nees) Bres., Ganoderma resinaceum Boud and Ganoderma applanatum (Pers.) Pat.) are traditional medicines with beneficial effects on immunoregulation, analgesia and the nervous system, but whether MORs are engaged in their effects remains unknown. AIM OF THE STUDY: This work aimed to identify MOR ligands among compounds isolated from the above-mentioned 10 species, and to investigate selectivity against four opioid receptor subtypes. By analyzing the structure-activity relationship and off-target effects, we could provide a new direction for the future development of MOR drugs. MATERIALS AND METHODS: Four opioid receptor subtype models, including MOR, delta (DOR), kappa (KOR) and nop (NOR), were established with a label-free phenotypic dynamic mass redistribution assay to systematically profile the pharmacological properties of known ligands. Then, 82 natural compounds derived from the 10 species were screened against MOR to identify new ligands. The selectivity of the new ligands was characterized against the four subtypes, and off-target effects were also investigated on eight G protein-coupled receptors (GPCRs). RESULTS: The pharmacological properties of known ligands on transfected HEK293T-MOR, HEK293-DOR, HEK293-KOR and HEK293-NOR cell lines were characterized. Seven compounds purified from Ganoderma cochlear (Blume et Nees) Bres. and Carthamus tinctorius L were MOR antagonists with micromolar potency. Among them, compound 35 showed the strongest antagonistic activity on MOR with an IC50 value of 10.0 ± 3.0 µM. To a certain extent, these seven new antagonists, exhibited antagonistic activity on the other opioid receptor subtypes, and they had almost no effect on other GPCRs, including CB1, CB2, M2 and beta2AR. Additionally, a compound from Lepidium meyenii Walp. displayed MOR agonistic activity. CONCLUSIONS: The established screening models opened new avenues for the discovery and evaluation of opioid receptor ligand selectivity. Together, the novel MOR antagonists and agonists will enrich the inventory of MOR ligands and benefit related therapies.


Assuntos
Produtos Biológicos/farmacologia , Antagonistas de Entorpecentes/farmacologia , Receptores Opioides mu/agonistas , Receptores Opioides mu/antagonistas & inibidores , Receptores Opioides/metabolismo , Produtos Biológicos/química , Técnicas Biossensoriais/métodos , Descoberta de Drogas/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Células HEK293 , Humanos , Ligantes , Receptores Opioides/agonistas , Receptores Opioides/genética , Relação Estrutura-Atividade
20.
Mediators Inflamm ; 2021: 6699499, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33510583

RESUMO

Method: Mice were randomly assigned to the sham, I/R, Oxy, and I/R with Oxy groups. Oxy was injected intraperitoneally 30 min before tourniquet placement. Morphological changes of the gastrocnemius muscle in these mice were assessed by hematoxylin-eosin (HE) staining and electron microscopy. Expression levels of TLR4, NF-κB, SIRT1, and PGC-1α in the skeletal muscles were detected by western blot. Blood TNF-α levels, gastrocnemius muscle contractile force, and ATP concentration were examined. Results: Compared with the I/R group, Oxy pretreatment attenuated skeletal muscle damage, decreased serum TNF-α levels, and inhibited the expression levels of TLR4/NF-κB in the gastrocnemius muscle. Furthermore, Oxy treatment significantly increased serum ATP levels and the contractility of the skeletal muscles. SIRT1 and PGC-1α levels were significantly reduced in gastrocnemius muscle after I/R. Oxy pretreatment recovered these protein expression levels. Conclusion: Tourniquet-induced acute limb I/R results in morphological and functional impairment in skeletal muscle. Pretreatment with Oxy attenuates skeletal muscle from acute I/R injury through inhibition of TLR4/NF-κB-dependent inflammatory response and protects SIRT1/PGC-1α-dependent mitochondrial function.


Assuntos
Contração Muscular , Músculo Esquelético/metabolismo , Receptores Opioides/metabolismo , Traumatismo por Reperfusão/metabolismo , Torniquetes , Trifosfato de Adenosina/metabolismo , Animais , Inflamação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica , Músculo Esquelético/lesões , Subunidade p50 de NF-kappa B/metabolismo , Perfusão , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Sirtuína 1/metabolismo , Receptor 4 Toll-Like/metabolismo
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