RESUMO
In the pursuit of new lead compounds with fewer side effects than opioids, the novel synthetic phytochemical core, 3,3-dibromoflavanone (3,3-DBF), has emerged as a promising candidate for pain management. Acute assays demonstrated dose-dependent central and peripheral antinociceptive activity of 3,3-DBF through the µ-opioid receptor. This study aimed to explore repeated administration effects of 3,3-DBF in mice and compare them with morphine. Mice were treated with 3,3-DBF (30 mg/kg), morphine (6 mg/kg), or vehicle for 10 days, alongside single-treatment groups. Unlike morphine, 3,3-DBF demonstrated antinociceptive effects in the hot plate test without inducing tolerance. Locomotor activity and motor coordination tests (evaluated through the inverted screen and rotarod tests) revealed no significant differences between the 3,3-DBF-treated and control groups. The gastrointestinal transit assay indicated that 3,3-DBF did not induce constipation, in contrast to morphine. Furthermore, withdrawal signs assessed with the Gellert-Holtzman scale were not comparable to morphine. Additionally, 3,3-DBF exhibited antidepressant-like activity, reducing immobility time in the forced swimming and tail suspension tests, akin to imipramine. In summary, 3,3-DBF demonstrated antinociceptive effects without inducing tolerance or dependence and exhibited antidepressant properties. These findings highlight the potential of 3,3-DBF as a promising therapeutic agent for pain management and its comorbidities, offering advantages over morphine by minimizing side effects.
Assuntos
Analgésicos , Antidepressivos , Flavonoides , Morfina , Animais , Morfina/farmacologia , Morfina/uso terapêutico , Camundongos , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Antidepressivos/química , Masculino , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Analgésicos/química , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Flavonoides/química , Dor/tratamento farmacológico , Manejo da Dor/métodos , Atividade Motora/efeitos dos fármacosRESUMO
Anxiety disorders, depression and pain are highly prevalent pathologies. Their pharmacotherapy is associated with unwanted side effects; hence there is a clinical need to develop more effective drugs with fewer adverse reactions. Chalcones are one of the major classes of naturally occurring compounds. Chalcones and their derivatives have a huge importance in medicinal chemistry, displaying a wide range of pharmacological activities including anti-inflammatory, antimicrobial, antioxidant, cytotoxic and antitumor actions. The aim of this work was to evaluate chalcone effects on different targets involved in these pathologies. We have synthesized a series of simple chalcone derivatives taking common structural requirements described in literature related to their anxiolytic-like, antidepressant-like and/or antinociceptive properties into account. Furthermore, their potential in vitro effects towards different targets involved in these pathologies were evaluated. We have obtained twenty chalcones with moderate to high yields and assessed their ability to bind distinctive receptors, from rat brain homogenates, by displacement of labelled specific ligands: [3H] FNZ (binding site of benzodiazepines/GABAA), [3H] 8-OH-DPAT (serotonin 5-HT1A) and [3H] DAMGO (µ-opioid). Those compounds that showed the better in vitro activities were evaluated in mice using different behavioural tasks. In vivo results showed that 5'-methyl-2'-hydroxychalcone (9) exerted anxiolytic-like effects in mice in the plus maze test. While chalcone nuclei (1) revealed antidepressant-like activities in the tail suspension test. In addition, the novel 5'-methyl-2'-hydroxy-3'-nitrochalcone (12) exhibited antinociceptive activity in acute chemical and thermal nociception tests (writhing and hot plate tests). In conclusion, chalcones are thus promising compounds for the development of novel drugs with central nervous system (CNS) actions.
RESUMO
The pharmacotherapy for the treatment of pain is an active area of investigation. There are effective drugs to treat this problem, but there is also a need to find alternative treatments free of undesirable side effects. In the present work the capacity of a series of flavonoids to bind to the µ opioid receptor was evaluated. The most active compound, 3,3-dibromoflavanone (31), a synthetic flavonoid, presented a significant inhibition of the binding of the selective µ opioid ligand [(3)H]DAMGO, with a Ki of 0.846 ± 0.263 µM. Flavanone 31 was further synthesized using a simple and cheap procedure with good yield. Its in vivo effects in mice, after acute treatments, were studied using antinociceptive and behavioral assays. It showed no sedative, anxiolytic, motor incoordination effects or inhibition of the gastrointestinal transit in mice at the doses tested. It evidenced antinociceptive activity on the acetic acid-induced nociception, hot plate and formalin tests (at 10 mg/kg and 30 mg/kg). The results showed that the 5-HT2 receptor and the adrenoceptors seem unlikely to be involved in its antinociceptive effects. Naltrexone, a nonselective opioid receptors antagonist, totally blocked compound 31 antinociceptive effects on the hot plate test, but naltrindole (δ opioid antagonist) and nor-binaltorphimine (κ opioid antagonist) did not. These findings demonstrated that 3,3-dibromoflavanone (31), at doses that did not interfere with the motor performance, exerted clear dose dependent antinociception when assessed in the chemical and thermal models of nociception in mice and it seems that its action is related to the activation of the µ opioid receptor.
Assuntos
Analgésicos/uso terapêutico , Flavonoides/uso terapêutico , Receptores Opioides mu/metabolismo , Dor Visceral/metabolismo , Ácido Acético/farmacologia , Analgésicos/farmacologia , Analgésicos Opioides/farmacocinética , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Composição de Medicamentos , Ala(2)-MePhe(4)-Gly(5)-Encefalina/farmacocinética , Flavanonas/farmacologia , Flavanonas/uso terapêutico , Flavonoides/química , Flavonoides/farmacologia , Trânsito Gastrointestinal/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Atividade Motora/efeitos dos fármacos , Naltrexona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Ligação Proteica/efeitos dos fármacos , Trítio/farmacocinética , Dor Visceral/diagnóstico , Dor Visceral/tratamento farmacológicoRESUMO
Benzodiazepines are the most widely prescribed class of psychoactive drugs in current therapeutic use, despite the important unwanted side effects that they produce, such as sedation, myorelaxation, ataxia, amnesia, and ethanol and barbiturate potentiation and tolerance. They exert their therapeutic effects via binding to the benzodiazepine binding site of gamma-aminobutyric acid (GABA) type A receptors, and allosterically modulating the chloride flux through the ion channel complex. First isolated from plants used as tranquilizers in folkloric medicine, some natural flavonoids have been shown to possess selective affinity for the benzodiazepine binding site with a broad spectrum of central nervous system effects. Since the initial search for alternative benzodiazepine ligands amongst the flavonoids, a list of successful synthetic derivatives has been generated with enhanced activities. This review provides an update on research developments that have established the activity of natural and synthetic flavonoids on GABA type A receptors. Flavonoids are prominent drugs in the treatment of mental disorders, and can also be used as tools to study modulatory sites at GABA type A receptors and to develop GABA type A selective agents further.
RESUMO
Hesperidin (HN) is a flavanone glycoside abundantly found in citrus fruits. This flavonoid mediated central nervous system activity following intraperitoneal (i.p.) acute treatment. The responses of mice after the chronic i.p. (4 and 30 mg/kg/day) or the oral intake administration of this drug (20, 50 and 100 mg/kg/day) were studied by using the holeboard, the plus-maze and the locomotor activity tests. Hesperidin, chronically administered by the i.p. route, exerted a decrease in the locomotor and exploratory activities, thus evidencing a depressant activity. In turn, the chronic oral intake of this flavonoid induced anxiolytic-like effects. These varied responses could be attributed to the different routes of administration that could lead to the production of diverse active metabolites.
Assuntos
Sistema Nervoso Central/efeitos dos fármacos , Hesperidina/farmacologia , Aprendizagem em Labirinto/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Administração Oral , Animais , Injeções Intraperitoneais , Masculino , CamundongosRESUMO
A set of sulfamides designed, synthesized and evaluated against maximal electroshock seizure (MES) and pentilenetetrazol (PTZ) tests with promising results, were tested for their affinity for the benzodiazepine binding site of the GABA(A) receptor. The most active compounds, N,N'-dicyclohexylsulfamide (7) and N,N'-diphenethylsulfamide (10), competitively inhibited the binding of [(3)H]-flunitrazepam to the benzodiazepine binding site with K(i)±SEM values of 27.7±4.5µM (n=3) and 6.0±1.2µM (n=3), respectively. The behavioral actions of these sulfamides, i.p. administered in mice, were examined in the plus-maze, hole-board and locomotor activity assays. Compound 7 exhibited anxiolytic-like effects in mice evidenced by a significant increase of the parameters measured in the hole-board test (at 1 and 3mg/kg) and the plus-maze assay (at 1 and 3mg/kg). Compound 10 evidenced anxiolytic activity in the plus-maze and the hole-board tests at 1mg/kg. Locomotor activity of mice was not modified by compound 7 or 10 at the doses tested. Flumazenil, a non selective benzodiazepine binding site antagonist, was able to completely reverse the anxiolytic-like effects of these sulfamides, proving that the GABA(A) receptor is implicated in this action. Anxiety represents a major problem for people with epilepsy. The use of anxiolytic and anticonvulsant sulfamides would be beneficial to individuals who suffer from both disorders.
Assuntos
Ansiolíticos/metabolismo , Anticonvulsivantes/metabolismo , Ansiedade/metabolismo , Benzodiazepinas/metabolismo , Receptores de GABA-A/metabolismo , Sulfonamidas/metabolismo , Animais , Ansiolíticos/química , Ansiolíticos/uso terapêutico , Anticonvulsivantes/química , Anticonvulsivantes/uso terapêutico , Ansiedade/tratamento farmacológico , Ansiedade/psicologia , Sítios de Ligação/efeitos dos fármacos , Sítios de Ligação/fisiologia , Flunitrazepam/química , Flunitrazepam/metabolismo , Flunitrazepam/uso terapêutico , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Sulfonamidas/química , Sulfonamidas/uso terapêuticoRESUMO
This paper extended the evaluation of the depressant and antinociceptive activities of hesperidin in order to determine its effectiveness by the intraperitoneal and oral routes, its pharmacological interaction with diverse pathways of neurotransmission and the role of its aglycone, hesperetin. The capacity of hesperidin and hesperetin to bind to µ-opioid receptor and their actions on µ-opioid receptor co-expressed with GIRK1/GIRK2 channels (G protein-activated inwardly rectifying K+ channels) in Xenopus laevis oocytes were also determined. Hesperidin exhibited a depressant activity in the hole board and locomotor activity tests, antinociceptive activities in the abdominal writhing and hot plate tests and no motor incoordination in the inverted screen and rotarod assays, only by the intraperitoneal route. Hesperetin did not show any effects in vivo in mice in these models, but in vitro it displaced the [³H]DAMGO binding with low-affinity and inhibited inward currents through the expressed GIRK1/2 channels. Although hesperidin actions in vivo demonstrated to be mediated by an opioid mechanism of action, it failed to directly bind to and activate the µ-opioid receptor or produce any change on inward GIRK1/2 currents in vitro. However, it should be considered that hesperidin may be metabolized, possibly resulting in crucial changes in its biological activity.
Assuntos
Analgésicos/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/antagonistas & inibidores , Hesperidina/metabolismo , Receptores Opioides mu/metabolismo , Analgésicos/farmacologia , Animais , Relação Dose-Resposta a Droga , Feminino , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/fisiologia , Hesperidina/farmacologia , Humanos , Masculino , Camundongos , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Bloqueadores dos Canais de Potássio/metabolismo , Bloqueadores dos Canais de Potássio/farmacologia , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , Ratos , Xenopus laevisRESUMO
Using the guide of a competitive assay for the benzodiazepine binding site in the γ-aminobutyric acid type A receptor (GABA(A)), two active diterpenes were isolated from the aerial parts of Aloysia virgata (Ruíz & Pavón) A.L. Jussieu var. platyphylla (Briquet) Moldenke. These compounds, identified as (16R)-16,17,18-trihydroxyphyllocladan-3-one (1) and (16R)-16,17-dihydroxyphyllocladan-3-one (2) on the basis of spectral data, competitively inhibited the binding of [(3)H]-FNZ to the benzodiazepine binding site with K(i)±S.E.M. values of 56±19 µM and 111±13 µM, respectively. The behavioral actions of these diterpenes, intraperitoneally (i.p.) administered in mice, were examined in the plus-maze, holeboard, locomotor activity and light/dark tests. Compound 1 exhibited anxiolytic-like effects in mice evidenced by a significant increase of the parameters measured in the holeboard test (the number of head dips at 0.3 mg/kg and 3 mg/kg, the rears at 1 mg/kg and the time spent head-dipping at 3 mg/kg), in the plus-maze assay (the percentage of open arm entries at 1 mg/kg) and in the light/dark test (the time in light and the number of transitions at 1 mg/kg). Compound 2 augmented the number of rearings in the holeboard apparatus (at 0.3 mg/kg and 1 mg/kg) and the locomotor activity (at 1 mg/kg). These results reveal the presence of neuroactive compounds in Aloysia virgata.
Assuntos
Ansiolíticos/farmacologia , Encéfalo/efeitos dos fármacos , Diterpenos/farmacologia , Extratos Vegetais/farmacologia , Receptores de GABA-A/efeitos dos fármacos , Verbenaceae/química , Animais , Ansiolíticos/metabolismo , Comportamento Animal/efeitos dos fármacos , Sítios de Ligação , Ligação Competitiva , Escuridão , Diterpenos/metabolismo , Flunitrazepam/metabolismo , Luz , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Modelos Animais , Atividade Motora/efeitos dos fármacos , Extratos Vegetais/metabolismo , Receptores de GABA-A/metabolismoRESUMO
INTRODUCTION: Fractioning of an extract of Valeriana pavonii, a native species used in Colombian folk medicine as tranquilizer, led to the isolation and identification of isovaleramide, one of the active constituents responsible for its central nervous system activity as anticonvulsant. OBJECTIVE: Description of the isolation and identification of isovaleramide, an active principle on central nervous system from Valeriana pavonii. MATERIALS AND METHODS: The purification of isovaleramide was carried out by chromatographic techniques. Its structural elucidation was determined by nuclear magnetic resonance and mass spectrometry. Maximal electroshock seizure was used as in vivo pharmacological test, additionally in vitro GABA-A/BDZ-binding site studies were performed. RESULTS: Isovaleramide was isolated from the most active fraction of Valeriana pavonii. This compound, at 100 mg/Kg, p.o, evidenced a 90% index protection against the maximal electroshock seizure in mice (MES), comparable to the reference agent: sodium phenytoin (20 mg/kg, p.o, 100%). In the in vitro assay, isovaleramide (300 µM) exhibited a 42% of inhibition of the binding of ³H-FNZ to its sites. CONCLUSION: Isovaleramide is one of the active anticonvulsant constituents of Valeriana pavonii, for the first time reported in this species. These results support the traditional use of Valeriana pavonii and its interest as a therapeutic source.
Assuntos
Amidas/isolamento & purificação , Anticonvulsivantes/isolamento & purificação , Valeriana/química , Animais , Masculino , CamundongosRESUMO
Introducción. El fraccionamiento fitoquímico de Valeriana pavonii, especie vegetal nativa utilizada tradicionalmente en Colombia con fines tranquilizantes, condujo al aislamiento e identificación de la isovaleramida, uno de los principios responsables de su actividad sobre el sistema nervioso central como anticonvulsivo. Objetivo. Reportar la identificaciòn de la isovaleramida, metabolito de V. pavonii activo sobre el sistema nervioso central.Materiales y métodos. La purificaciòn de la isovaleramida se realizó mediante técnicas cromatográficas. Su estrucutra se determinó por experimentos de resonancia magnética y espectrometría de masas. Se emplearon las pruebas de convulsión máxima inducida eléctricamente en ratones como ensayo farmacológico in vivo y el ensayo in vitro de unión al sitio de las benzodiacepinas sobre el receptor GABA-A. Resultados. En el modelo de convulsión máxima inducida eléctricamente en ratones, la isovaleramida, aislada de la fracción más activa de V. pavonii, confirió un índice de protección de 90 por ciento en una dosis de 100 mg/kg, por vía oral, comparable al agente de referencia utilizado: fenitoína sódica (20 mg/kg, por ví oral, 100 por ciento) y superior al control (vehículo, 20 por ciento). En el ensayo in vitro, la isovaleramida presentó un 42 por ciento de inhibición del sitio de unión de flunitracepam con tritio. Conclusión. La isovaleramida es uno de los principios activos anticonvulsivos de V. pavonii, por primera vez reportado en esta especie. Estos resultados dan soporte al uso tradicional de V. pavonii y a su interés como fuente de principios útiles en terapéutica.
Introduction. Fractioning of an extract of Valeriana pavonii, a native species used in Colombian folk medicine as tranquilizer, led to the isolation and identification of isovaleramide, one of the active constituents responsible for its central nervous system activity as anticonvulsant. Objective. Description of the isolation and identification of isovaleramide, an active principle on central nervous system from Valeriana pavonii. Materials and methods. The purification of isovaleramide was carried out by chromatographic techniques. Its structural elucidation was determined by nuclear magnetic resonance and mass spectrometry. Maximal electroshock seizure was used as in vivo pharmacological test, additionally in vitro GABA-A/BDZ-binding site studies were performed.Results. Isovaleramide was isolated from the most active fraction of Valeriana pavonii. This compound, at 100 mg/Kg, p.o, evidenced a 90 percent index protection against the maximal electroshock seizure in mice (MES), comparable to the reference agent: sodium phenytoin (20 mg/kg, p.o, 100 percent). In the in vitro assay, isovaleramide (300 ¦ÌM) exhibited a 42 percent of inhibition of the binding of 3H-FNZ to its sites. Conclusion. Isovaleramide is one of the active anticonvulsant constituents of Valeriana pavonii, for the first time reported in this species. These results support the traditional use of Valeriana pavonii and its interest as a therapeutic source.