RESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: The traditional use of plants for medicinal purposes, called phytomedicine, has been known to provide relief from pain. In Bangladesh, the Chakma indigenous community has been using Allophylus villosus and Mycetia sinensis to treat various types of pain and inflammation. AIM OF THE STUDY: The object of this research is to evaluate the effectiveness of these plants in relieving pain and their antioxidant properties using various approaches such as in vitro, in vivo, and computational techniques. Additionally, the investigation will also analyse the phytochemicals present in these plants. MATERIALS AND METHODS: We conducted in vivo analgesic experiment on Swiss albino mice and in-silico inhibitory activities on COX-2 & 15-LOX-2 enzymes. Assessment of DPPH, Anti Radical Activities (ARA), FRAP, H2O2 Free Radical Scavenging, Reducing the power of both plants performed significant % inhibition with tolerable IC50. Qualitative screening of functional groups of phytochemicals was précised by FTIR and GC-MS analysis demonstrated phytochemical investigations. RESULTS: The ethyl acetate (EtOAc) fractioned Mycetia sinensis extract as well as the ethanoic extract and all fractioned extracts of Allophylus villosus have reported a significant percentage (%) of writhing inhibition (p < 0.05) with the concentrated doses 250 mg as well as 500 mg among the Swiss albino mice for writhing observation of analgesic effect. In the silico observation, a molecular-docking investigation has performed according to GC-MS generated 43 phyto-compounds of both plants to screen their binding affinity by targeting COX-2 and 15-LOX-2 enzymes. Consequently, in order to assess and ascertain the effectiveness of the sorted phytocompounds, ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) investigation, DFT (Density-functional theory) by QM (Quantum mechanics), and MDS (Molecular dynamics simulation) were carried out. As the outcome, compounds like 5-(2,4-ditert-butylphenoxy)-5-oxopentanoic acid; 2,4-ditert-butylphenyl 5-hydroxypentanoate; 3,3-diphenyl-5-methyl-3H-pyrazole; 2-O-(6-methylheptan-2-yl) 1-O-octyl benzene-1,2-dicarboxylate and dioctan-3-yl benzene-1,2-dicarboxylate derived from the ethnic plant A. villosus and another ethnic plant M. sinensis extracts enchants magnificent analgesic inhibitions and performed more significant drug like activities with the targeted enzymes. CONCLUSIONS: Phytocompounds from A. villosus & M. sinensis exhibited potential antagonist activity against human 15-lipoxygenase-2 and cyclooxygenase-2 proteins. The effective ester compounds from these plants performed more potential anti-nociceptive activity which could be used as a drug in future.
Asunto(s)
Analgésicos , Antioxidantes , Extractos Vegetales , Animales , Antioxidantes/farmacología , Antioxidantes/aislamiento & purificación , Analgésicos/farmacología , Analgésicos/química , Extractos Vegetales/farmacología , Extractos Vegetales/química , Ratones , Masculino , Dolor/tratamiento farmacológico , Simulación del Acoplamiento Molecular , Fitoquímicos/farmacología , Fitoquímicos/análisis , Ciclooxigenasa 2/metabolismoRESUMEN
BACKGROUND: The Scutellaria genus has promising therapeutic capabilities as an aromatherapy. Based on that and local practices of S. nuristanica Rech. F. The essential oil was studied for the first time for its diverse biomedical applications. PURPOSE: This study aimed to evaluate and validate their therapeutic capabilities by screening the essential oil ingredients and examining their antimicrobial, antioxidant, carbonic anhydrase, and antidiabetic using further In silico assessment and In vivo anti-inflammatory and analgesic capabilities to devise novel sources as natural remedies alternative to the synthetic drugs. METHODS: Essential oil was obtained through hydrodistillation, and the constituents were profiled using GC-MS. The antimicrobial assessment was conducted using an agar well diffusion assay. Free radical scavenging capabilities were determined by employing DPPH and ABTS assay. The carbonic anhydrase-II was examined using colorimetric assay, while the antidiabetic significance was performed using α-Glucosidase assay. The anti-inflammatory significance was examined through carrageenan-induced paw edema, and the analgesic features of the essential oil were determined using an acetic acid-induced writhing assay. RESULTS: Fifty constituents were detected in S. nuristanica essential oil (SNEO), contributing 95.93 % of the total EO, with the predominant constituents being 24-norursa-3,12-diene (10.12 %), 3-oxomanoyl oxide (9.94 %), methyl 7-abieten-18-oate (8.85 %). SNEO presented significance resistance against the Gram-positive bacterial strains (GPBSs), Bacillus atrophaeus and Bacillus subtilis, as compared to the Salmonella typhi and Klebsiella pneumoniae, Gram-negative bacterial strains (GNBSs) as well as two fungal strains Aspergillus parasiticus and Aspergillus niger associated with their respective standards. Considerable free radical scavenging capacity was observed in DPPH compared to the ABTS assay when correlated with ascorbic acid. In addition, when equated with their standards, SNEO offered considerable in vitro carbonic anhydrase II and antidiabetic capabilities. Additionally, the antidiabetic behavior of the 9 dominant compounds of SNEO was tested via In silico techniques, such as molecular docking, which assisted in the assessment of the significance of binding contacts of protein with each chemical compound and pharmacokinetic evaluations to examine the drug-like characteristics. Molecular dynamic simulations at 100 ns and binding free energy evaluations such as PBSA and GBSA models explain the molecular mechanics and stability of molecular complexes. It was also observed that SNEO depicted substantial anti-inflammatory and analgesic capabilities. CONCLUSION: Hence, it was concluded that the SNEO comprises bioactive ingredients with biomedical significance, such as anti-microbial, antioxidant, CA-II, antidiabetic, anti-inflammatory, and analgesic agents. The computational validation also depicted that SNEO could be a potent source for the discovery of anti-diabetic drugs.
Asunto(s)
Antiinflamatorios , Antioxidantes , Edema , Hipoglucemiantes , Aceites Volátiles , Scutellaria , Animales , Scutellaria/química , Antioxidantes/farmacología , Antioxidantes/química , Antiinflamatorios/farmacología , Antiinflamatorios/química , Aceites Volátiles/farmacología , Aceites Volátiles/química , Hipoglucemiantes/farmacología , Hipoglucemiantes/química , Edema/tratamiento farmacológico , Analgésicos/farmacología , Analgésicos/química , Masculino , Ratones , Simulación del Acoplamiento Molecular , Carragenina , Cromatografía de Gases y Espectrometría de Masas , Antiinfecciosos/farmacología , Antiinfecciosos/química , Aromaterapia/métodos , Antibacterianos/farmacología , Antibacterianos/químicaRESUMEN
German chamomile (Matricaria chamomilla L.) is an essential oil- containing medicinal plant used worldwide. The aim of this study was to gain knowledge of the phytochemical composition and the analgesic and soporific activity of Matricaria chamomilla L. (German chamomile) flower extract and its amino acid preparations, to predict the mechanisms of their effects by molecular docking and to develop aqueous printing gels and novel 3D-printed oral dosage forms for the flower extracts. In total, 22 polyphenolic compounds and 14 amino acids were identified and quantified in the M. chamomilla extracts. In vivo animal studies with rodents showed that the oral administration of such extracts revealed the potential for treating of sleep disorders and diseases accompanied by pain. Amino acids were found to potentiate these effects. Glycine enhanced the analgesic activity the most, while lysine and ß-alanine improved the soporific activity. The molecular docking analysis revealed a high probability of γ-aminobutyric acid type A (GABAA) and N-methyl-D-aspartate (NMDA) receptor antagonism and 5-lipoxygenase (LOX-5) inhibition by the extracts. A polyethylene oxide (PEO)-based gel composition with the M. chamomilla extracts was proposed for preparing a novel 3D-printed dosage form for oral administration. These 3D-printed extract preparations can be used, for example, in dietary supplement applications.
Asunto(s)
Aminoácidos , Flores , Matricaria , Simulación del Acoplamiento Molecular , Fitoquímicos , Extractos Vegetales , Impresión Tridimensional , Extractos Vegetales/química , Extractos Vegetales/farmacología , Animales , Matricaria/química , Aminoácidos/química , Flores/química , Fitoquímicos/química , Fitoquímicos/farmacología , Ratas , Analgésicos/química , Analgésicos/farmacología , Masculino , RatonesRESUMEN
Local anesthetics (LA), as part of multimodal analgesia, have garnered significant interest for their role in delaying the initiation of opioid therapy, reducing postoperative opioid usage, and mitigating both hospitalization duration and related expenses. Despite numerous endeavors to extend the duration of local anesthetic effects, achieving truly satisfactory long-acting analgesia remains elusive. Drawing upon prior investigations, vesicular phospholipid gels (VPGs) emerge as promising candidates for extended-release modalities in small-molecule drug delivery systems. Therefore, we tried to use the amphiphilicity of phospholipids to co-encapsulate levobupivacaine hydrochloride and meloxicam, two drugs with different hydrophilicity, to obtain a long-term synergistic analgesic effect. Initially, the physicochemical attributes of the formulation were characterized, followed by an examination of its in vitro release kinetics, substantiating the viability of extending the release duration of the dual drugs. Sequentially, in vivo investigations encompassing pharmacokinetic profiling and assessment of analgesic efficacy were undertaken, revealing a prolonged release duration of up to 120 h and attainment of optimal postoperative analgesia. Subsequently, inquiries into the mechanism underlying synergistic analgesic effects and safety evaluations pertinent to the delivery strategy were pursued. In summation, we successfully developed a promising formulation to achieve long-acting analgesia.
Asunto(s)
Anestésicos Locales , Preparaciones de Acción Retardada , Liberación de Fármacos , Levobupivacaína , Meloxicam , Dolor Postoperatorio , Dolor Postoperatorio/tratamiento farmacológico , Anestésicos Locales/administración & dosificación , Anestésicos Locales/farmacocinética , Anestésicos Locales/química , Animales , Meloxicam/administración & dosificación , Meloxicam/farmacocinética , Masculino , Levobupivacaína/administración & dosificación , Fosfolípidos/química , Fosfolípidos/administración & dosificación , Ratas Sprague-Dawley , Bupivacaína/administración & dosificación , Bupivacaína/farmacocinética , Bupivacaína/química , Bupivacaína/análogos & derivados , Analgésicos/administración & dosificación , Analgésicos/química , Analgésicos/farmacocinética , Geles , Sinergismo FarmacológicoRESUMEN
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.
Asunto(s)
Analgésicos , Antidepresivos , Flavonoides , Morfina , Animales , Morfina/farmacología , Morfina/uso terapéutico , Ratones , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Antidepresivos/química , Masculino , Analgésicos/farmacología , Analgésicos/uso terapéutico , Analgésicos/química , Flavonoides/farmacología , Flavonoides/uso terapéutico , Flavonoides/química , Dolor/tratamiento farmacológico , Manejo del Dolor/métodos , Actividad Motora/efectos de los fármacosRESUMEN
Pain and inflammation contribute immeasurably to reduced quality of life, yet modern analgesic and anti-inflammatory therapeutics can cause dependence and side effects. Here, we screened 1444 plant extracts, prepared primarily from native species in California and the United States Virgin Islands, against two voltage-gated K+ channels - T-cell expressed Kv1.3 and nociceptive-neuron expressed Kv7.2/7.3. A subset of extracts both inhibits Kv1.3 and activates Kv7.2/7.3 at hyperpolarized potentials, effects predicted to be anti-inflammatory and analgesic, respectively. Among the top dual hits are witch hazel and fireweed; polymodal modulation of multiple K+ channel types by hydrolysable tannins contributes to their dual anti-inflammatory, analgesic actions. In silico docking and mutagenesis data suggest pore-proximal extracellular linker sequence divergence underlies opposite effects of hydrolysable tannins on different Kv1 isoforms. The findings provide molecular insights into the enduring, widespread medicinal use of witch hazel and fireweed and demonstrate a screening strategy for discovering dual anti-inflammatory, analgesic small molecules.
Asunto(s)
Analgésicos , Antiinflamatorios , Extractos Vegetales , Antiinflamatorios/farmacología , Antiinflamatorios/química , Analgésicos/farmacología , Analgésicos/química , Animales , Extractos Vegetales/farmacología , Extractos Vegetales/química , Humanos , Ratones , Coriandrum/química , Simulación del Acoplamiento Molecular , Plantas Medicinales/química , Bloqueadores de los Canales de Potasio/farmacología , Bloqueadores de los Canales de Potasio/química , Masculino , Taninos/farmacología , Taninos/químicaRESUMEN
Although phytochemicals are plant-derived toxins that are primarily produced as a form of defense against insects or microbes, several lines of study have demonstrated that the phytochemical, quercetin, has several beneficial biological actions for human health, including antioxidant and inflammatory effects without side effects. Quercetin is a flavonoid that is widely found in fruits and vegetables. Since recent studies have demonstrated that quercetin can modulate neuronal excitability in the nervous system, including nociceptive sensory transmission via mechanoreceptors and voltage-gated ion channels, and inhibit the cyclooxygenase-2-cascade, it is possible that quercetin could be a complementary alternative medicine candidate; specifically, a therapeutic agent against nociceptive and pathological pain. The focus of this review is to elucidate the neurophysiological mechanisms underlying the modulatory effects of quercetin on nociceptive neuronal activity under nociceptive and pathological conditions, without inducing side effects. Based on the results of our previous research on trigeminal pain, we have confirmed in vivo that the phytochemical, quercetin, demonstrates (i) a local anesthetic effect on nociceptive pain, (ii) a local anesthetic effect on pain related to acute inflammation, and (iii) an anti-inflammatory effect on chronic pain. In addition, we discuss the contribution of quercetin to the relief of nociceptive and inflammatory pain and its potential clinical application.
Asunto(s)
Fitoquímicos , Quercetina , Quercetina/farmacología , Quercetina/uso terapéutico , Quercetina/química , Humanos , Animales , Fitoquímicos/farmacología , Fitoquímicos/uso terapéutico , Fitoquímicos/química , Dolor/tratamiento farmacológico , Dolor Nociceptivo/tratamiento farmacológico , Analgésicos/farmacología , Analgésicos/uso terapéutico , Analgésicos/química , Inflamación/tratamiento farmacológico , Nocicepción/efectos de los fármacos , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Antiinflamatorios/químicaRESUMEN
This study investigates the anti-inflammatory, analgesic, and antioxidant properties of polyphenols extracted from Brassica oleracea var. capitata (cabbage) ethanolic extract (BOE). Given the historical use of cabbage in traditional medicine for treating various ailments, this research aims to validate these effects scientifically. The study involved the characterization of BOE's bioactive compounds using Fourier Transform Infrared Spectroscopy (FTIR) and Liquid Chromatography-Diode Array Detection-Electro-Spray Ionization Mass Spectrometry (HPLC-DAD-ESI MS) analysis. We assessed the anti-inflammatory and analgesic effects of topical and oral BOE administration on rodent models with acute and subacute inflammation. Additionally, the antioxidant capacity of orally administered BOE was evaluated. The results showed that BOE possesses significant levels of phenolic compounds with a potent antioxidant activity. The topical administration of BOE demonstrated notable anti-inflammatory effects in the tested rodent models, which were comparable with nonsteroidal anti-inflammatory drugs. These findings suggest that BOE could be a valuable natural remedy for inflammation-related conditions, supporting its traditional uses and highlighting its potential for further pharmacological development.
Asunto(s)
Analgésicos , Antiinflamatorios , Antioxidantes , Brassica , Inflamación , Extractos Vegetales , Polifenoles , Animales , Polifenoles/farmacología , Polifenoles/química , Extractos Vegetales/farmacología , Extractos Vegetales/química , Antioxidantes/farmacología , Antioxidantes/química , Brassica/química , Analgésicos/farmacología , Analgésicos/química , Antiinflamatorios/farmacología , Antiinflamatorios/química , Inflamación/tratamiento farmacológico , Ratones , Ratas , Masculino , Modelos Animales de EnfermedadRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Manilkara zapota (L.) P. Royen, also termed sapodilla or chikoo, is a significant plant in ethnomedicine because of its long history of traditional medical applications. In diverse cultures, sapodilla is believed to protect against oxidative stress, inflammation, and some chronic diseases because of its high antioxidant content. The naturally occurring antioxidant myricitrin (MYR) flavonoid is primarily found in the leaves and other plant parts of sapodilla and it is well-known for having therapeutic qualities and possible health advantages. AIM OF THE STUDY: To appraise the possible impact of MYR on a rat model of reserpine-induced fibromyalgia (FM) and explore its mechanism of action. MATERIALS AND METHODS: Isolation and identification of MYR with more than 99% purity from Manilkara zapota leaves were primarily done and confirmed through chromatographic and spectrophotometric techniques. To develop FM model, reserpine (RSP) was injected daily (1 mg/kg, s.c.) for three successive days. Then, MYR (10 mg/kg, i.p.) and pregabalin (PGB, 30 mg/kg, p.o.) were given daily for another five days. Behavioral changes were assessed through open field test (OFT), hot plate test, and forced swimming test (FST). Further analyses of different brain parameters and signaling pathways were performed to assess monoamines levels, oxidative stress, inflammatory response, apoptotic changes as well as silent information regulator 1 (SIRT1) and micro RNAs (miRNAs) expressions. RESULTS: From High-Performance Liquid Chromatography (HPLC) analysis, the methanol extract of sapodilla leaves contains 166.17 µg/ml of MYR. Results of behavioral tests showed a significant improvement in RSP-induced nociceptive stimulation, reduced locomotion and exploration and depressive-like behavior by MYR. Biochemical analyses showed that MYR significantly ameliorated the RSP-induced imbalance in brain monoamine neurotransmitters. In addition, MYR significantly attenuated oxidative stress elicited by RSP via up-regulating nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) protein expressions, enhancing superoxide dismutase (SOD) and catalase (CAT) activities, and reducing malondialdehyde (MDA) content in brain. The RSP-provoked inflammatory response was also diminished by MYR treatment as shown by a significant decreased NOD-like receptor protein 3 (NLRP3) inflammasome expression along with reduced levels of interleukin 1 beta (IL-1ß) and nuclear factor-κB (NF-κB). Furthermore, the anti-apoptotic activity of MYR was demonstrated by a marked rise in Bcl-2-associated X protein (BAX)/B cell lymphoma-2 (Bcl-2) ratio by lowering Bcl-2 while increasing BAX levels. In addition, MYR treatment significantly boosted the expression of SIRT1 deacetylase in RSP-treated animals. Interestingly, molecular docking showed the ability of MYR to form a stable complex in the binding site of SIRT1. Regarding miRNAs, MYR effectively ameliorated RSP-induced changes in miR-320 and miR-107 gene expressions. CONCLUSION: Our findings afford new insights into the anti-nociceptive profile of MYR in the RSP-induced FM model in rats. The underlying mechanisms involved direct binding and activation of SIRT1 to influence different signaling cascades, including Nrf2 and NF-κB/NLRP3 together with modulation of miRNAs. However, more in-depth studies are needed before proposing MYR as a new clinically relevant drug in the management of FM.
Asunto(s)
Analgésicos , Modelos Animales de Enfermedad , Fibromialgia , Flavonoides , MicroARNs , Reserpina , Sirtuina 1 , Animales , Sirtuina 1/metabolismo , Sirtuina 1/genética , Fibromialgia/tratamiento farmacológico , Fibromialgia/inducido químicamente , Analgésicos/farmacología , Analgésicos/uso terapéutico , Analgésicos/química , Ratas , Flavonoides/farmacología , Flavonoides/uso terapéutico , MicroARNs/metabolismo , MicroARNs/genética , Masculino , Hojas de la Planta/química , Extractos Vegetales/farmacología , Extractos Vegetales/química , Extractos Vegetales/uso terapéutico , Femenino , Conducta Animal/efectos de los fármacos , Ratas Wistar , Estrés Oxidativo/efectos de los fármacosRESUMEN
Soluble epoxide hydrolase (sEH) and HDAC6 mediate the NF-κB pathway in inflammatory responses, and their inhibitors exhibit powerful anti-inflammatory and analgesic activities in treating both inflammation and pain. Therefore, a series of dual-targeting inhibitors containing urea or squaramide and hydroxamic acid moieties were designed and synthesized, and their role as a new sEH/HDAC6 dual-targeting inhibitor in inflammatory pain was evaluated in a formalin-induced mice model and a xylene-induced mouse ear swelling model. Among them, compounds 28g and 28j showed the best inhibitory and selectivity of sEH and HDAC6. Compound 28g had satisfactory pharmacokinetic characteristics in rats. Following administration at 30 mg/kg, compound 28g exhibited more effective analgesic activity than either an sEH inhibitor (GL-B437) or an HDAC6 inhibitor (Rocilinostat) alone and coadministration of both inhibitors. Thus, these novel sEH/HDAC6 dual-targeting inhibitors exhibited powerful analgesic activity in nociceptive behavior and are worthy of further development.
Asunto(s)
Analgésicos , Diseño de Fármacos , Epóxido Hidrolasas , Histona Desacetilasa 6 , Inhibidores de Histona Desacetilasas , Inflamación , Dolor , Animales , Histona Desacetilasa 6/antagonistas & inhibidores , Histona Desacetilasa 6/metabolismo , Dolor/tratamiento farmacológico , Ratones , Inflamación/tratamiento farmacológico , Analgésicos/síntesis química , Analgésicos/farmacología , Analgésicos/uso terapéutico , Analgésicos/farmacocinética , Analgésicos/química , Masculino , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/química , Inhibidores de Histona Desacetilasas/uso terapéutico , Inhibidores de Histona Desacetilasas/farmacocinética , Epóxido Hidrolasas/antagonistas & inhibidores , Epóxido Hidrolasas/metabolismo , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , HumanosRESUMEN
Neuropathic pain is a high-intensity pain that can be caused by compression, transection, injury, nerve infiltration and drug treatment of cancer. Furthermore, drug therapy has low clinical efficacy, many adverse effects and remission of painful symptoms. In this way, natural products derived from plants constitute a promising therapeutic alternative. Therefore, the aim of this study was to evaluate the antihyperalgesic effect of γ-terpinene (γ-TPN) e γ-terpinene in ß-cyclodextrin inclusion complexes (TPN/CD) on neuropathic pain induced by tumor cells. Complexation extended the effect time for another 5 h and daily treatment for six days with γ-TPN (50 mg/kg, p.o.) and γ-TPN/ß-CD (50 mg/kg, p.o.) significantly reduced (p < 0.001) the mechanical hyperalgesia induced by the administration of 2x106 sarcoma cells 180 in the around the sciatic nerve. In addition, the Grip and Rota-rod techniques demonstrated that there was no interference on the muscle strength and motor coordination of the animals, suggesting that the compound under study does not have central nervous system depressant effects at the doses used. Molecular docking studies demonstrate favorable binding energies between γ-TPN and ß-CD, and alpha-2 adrenergic, glutamatergic, opioid and cholinergic receptors. Thus, this study demonstrates the potential of terpinene complexation in controlling neuropathic pain induced by tumor cells.
Asunto(s)
Monoterpenos Ciclohexánicos , Hiperalgesia , Monoterpenos , Neuralgia , beta-Ciclodextrinas , Animales , beta-Ciclodextrinas/química , beta-Ciclodextrinas/administración & dosificación , Neuralgia/tratamiento farmacológico , Hiperalgesia/tratamiento farmacológico , Masculino , Monoterpenos/farmacología , Monoterpenos/química , Monoterpenos/administración & dosificación , Ratones , Analgésicos/farmacología , Analgésicos/química , Analgésicos/administración & dosificación , Modelos Animales de Enfermedad , Nervio Ciático/efectos de los fármacos , Nervio Ciático/lesiones , Línea Celular Tumoral , Simulación del Acoplamiento Molecular , Sarcoma 180/tratamiento farmacológico , Sarcoma 180/patologíaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Plant vernacular names can provide clues about the popular use of a species in different regions and are valuable sources of information about the culture or vocabulary of a population. Several medicinal plants in Brazil have received names of medicines and brand-name products. AIM OF THE STUDY: The present work aimed to evaluate the chemical composition and pharmacological activity in the central nervous system of three species known popularly by brand names of analgesic, anti-inflammatory, antispasmodic, and digestive drugs. MATERIALS AND METHODS: Hydroethanolic extracts of Alternanthera dentata (AD), Ocimum carnosum (OC), and Plectranthus barbatus (PB) aerial parts were submitted to phytochemical analysis by HPLC-PAD-ESI-MS/MS and evaluated in animal models at doses of 500 and 1000 mg/kg. Mice were tested on hot plate, acetic acid-induced writing, formalin-induced licking, and intestinal transit tests. Aspirin and morphine were employed as standard drugs. RESULTS: The three extracts did not change the mice's response on the hot plate. Hydroethanolic extracts of AD and PB reduced the number of writhes and licking time, while OC was only effective on the licking test at dose of 1000 mg/kg. In addition, AD and OC reduced intestinal transit, while PB increased gut motility. CONCLUSIONS: Pharmacological tests supported some popular uses, suggesting peripheral antinociceptive and anti-inflammatory effects, while the phytochemical analysis showed the presence of several flavonoids in the three hydroethanolic extracts and steroids in PB, with some barbatusterol derivatives described for the first time in the species.
Asunto(s)
Amaranthaceae , Analgésicos , Antiinflamatorios , Parasimpatolíticos , Fitoquímicos , Componentes Aéreos de las Plantas , Extractos Vegetales , Plectranthus , Animales , Extractos Vegetales/farmacología , Extractos Vegetales/química , Analgésicos/farmacología , Analgésicos/química , Ratones , Parasimpatolíticos/farmacología , Antiinflamatorios/farmacología , Antiinflamatorios/química , Masculino , Amaranthaceae/química , Plectranthus/química , Fitoquímicos/farmacología , Fitoquímicos/análisis , Dolor/tratamiento farmacológico , Ocimum/química , Espectrometría de Masas en Tándem , Brasil , Tránsito Gastrointestinal/efectos de los fármacosRESUMEN
The effective management of moderate to severe pain often relies on the use of analgesic agents. However, the widespread utility of these medications is hindered by the occurrence of several undesirable side effects. In light of this challenge, there is growing interest in the development of κ opioid receptor (KOR) agonists, which have shown promise in mitigating these adverse effects. In this study, leveraging the structural scaffold of compound D (our previous study), we embarked on the design, synthesis, and evaluation of a series of N'-benzyl-3-chloro-N- ((1S,3R,4R)-3-((dimethylamino)methyl)-4-hydroxy-4-(3-methoxyphenyl)cyclohexyl)benzenesulfonamide derivatives. These compounds were subjected to comprehensive in vitro and in vivo test. Through systematic structure-activity relationship (SAR) exploration, we successfully identified compound 23p (Ki(KOR):1.9 nM) as a highly selective KOR ligand of new chemotype. 23p showed high clearance in vitro PK test, and abdominal contraction test showed potent antinociceptive effect. 23p and its O-demethyl metabolite 25 were both found in the plasma of mouse, 25 also showed potent affinity toward KOR (Ki(KOR): 3.1 nM), both they contribute to the analgesic effect. Moreover, 23p exhibited potent antinociceptive activity in abdominal constriction test, which was effectively abolished by pre-treatment of nor-BNI, a selective KOR antagonist.
Asunto(s)
Bencenosulfonamidas , Receptores Opioides kappa , Sulfonamidas , Animales , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacología , Sulfonamidas/síntesis química , Ligandos , Receptores Opioides kappa/metabolismo , Receptores Opioides kappa/antagonistas & inhibidores , Ratones , Masculino , Estructura Molecular , Humanos , Descubrimiento de Drogas , Relación Dosis-Respuesta a Droga , Analgésicos/farmacología , Analgésicos/química , Analgésicos/síntesis química , RatasRESUMEN
Tropomyosin receptor kinases (Trks) are receptor tyrosine kinases activated by neurotrophic factors, called neurotrophins. Among them, TrkA interacts with the nerve growth factor (NGF), which leads to pain induction. mRNA-display screening was carried out to discover a hit compound 2, which inhibits protein-protein interactions between TrkA and NGF. Subsequent structure optimization improving phosphorylation inhibitory activity and serum stability was pursued using a unique process that took advantage of the peptide being synthesized by translation from mRNA. This gave peptide 19, which showed an analgesic effect in a rat incisional pain model. The peptides described here can serve as a new class of analgesics, and the structure optimization methods reported provide a strategy for discovering new peptide drugs.
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Receptor trkA , Receptor trkA/antagonistas & inhibidores , Receptor trkA/metabolismo , Animales , Ratas , Humanos , Relación Estructura-Actividad , Descubrimiento de Drogas , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/síntesis química , Analgésicos/farmacología , Analgésicos/química , Analgésicos/síntesis química , Péptidos Cíclicos/farmacología , Péptidos Cíclicos/química , Péptidos Cíclicos/síntesis química , Masculino , Factor de Crecimiento Nervioso/metabolismo , Fosforilación , Dolor/tratamiento farmacológico , Ratas Sprague-DawleyRESUMEN
Transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel, which is considered a highly validated target for pain perception. Repeated activation with agonists to desensitize receptors or use the antagonists can both exert analgesic effects. In this work, two series of novel phenylpiperazine derivatives were designed, synthesized, and evaluated for the in vitro receptor inhibitory activity and in vivo analgesic activity. Among them, L-21 containing sulfonylurea group was identified with potent TRPV1 antagonistic activity and analgesic activity in various pain models. At the same time, L-21 exhibited low risk of hyperthermia side effect. These results indicated that L-21 is a promising candidate for further development of novel TRPV1 antagonist to treat pain.
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Analgésicos , Piperazinas , Canales Catiónicos TRPV , Canales Catiónicos TRPV/antagonistas & inhibidores , Canales Catiónicos TRPV/metabolismo , Piperazinas/química , Piperazinas/farmacología , Piperazinas/síntesis química , Animales , Ratones , Analgésicos/farmacología , Analgésicos/química , Analgésicos/síntesis química , Humanos , Dolor/tratamiento farmacológico , Relación Estructura-Actividad , Masculino , Células HEK293 , RatasRESUMEN
The novel cinnamic acid (CA) (H4-CA, H5-CA, and H7-CA) and caffeic acid (KA) (H4-KA, H5-KA, and H7-KA) hemorphin analogs have recently been synthesized and their trans isomers have been tested for antiseizure and antinociceptive activity. In the present study, the cis forms of these compounds were tested and compared with their trans isomers in seizure and nociception tests in mice. The cis-H5-CA and H7-CA compounds showed efficacy against psychomotor seizures, whereas the trans isomers were ineffective. Both the cis and trans KA isomers were ineffective in the 6-Hz test. In the maximal electroshock (MES) test, the cis isomers showed superior antiseizure activity to the trans forms of CA and KA conjugates, respectively. The suppression of seizure propagation by cis-H5-CA and the cis-H5-KA was reversed by a kappa opioid receptor (KOR) antagonist. Naloxone and naltrindole were not effective. The cis-isomers of CA conjugates and cis-H7-KA produced significantly stronger antinociceptive effects than their trans-isomers. The cis-H5-CA antinociception was blocked by naloxone in the acute phase and by naloxone and KOR antagonists in the inflammatory phase of the formalin test. The antinociception of the KA conjugates was not abolished by opioid receptor blockade. None of the tested conjugates affected the thermal nociceptive threshold. The results of the docking analysis also suggest a model-specific mechanism related to the activity of the cis-isomers of CA and KA conjugates in relation to opioid receptors. Our findings pave the way for the further development of novel opioid-related antiseizure and antinociceptive therapeutics.
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Analgésicos , Anticonvulsivantes , Ácidos Cafeicos , Cinamatos , Convulsiones , Animales , Analgésicos/farmacología , Analgésicos/química , Analgésicos/síntesis química , Anticonvulsivantes/farmacología , Anticonvulsivantes/química , Anticonvulsivantes/síntesis química , Ratones , Masculino , Convulsiones/tratamiento farmacológico , Cinamatos/farmacología , Cinamatos/química , Cinamatos/síntesis química , Cinamatos/uso terapéutico , Ácidos Cafeicos/farmacología , Ácidos Cafeicos/química , Ácidos Cafeicos/uso terapéutico , Ácidos Cafeicos/síntesis química , Péptidos/farmacología , Péptidos/química , Péptidos/síntesis química , Péptidos/uso terapéutico , Simulación del Acoplamiento Molecular , IsomerismoRESUMEN
The dorsal root ganglion (DRG) is the primary neuron responsible for transmitting peripheral pain signals to the central nervous system and plays a crucial role in pain transduction. Modulation of DRG excitability is considered a viable approach for pain management. Neuronal excitability is intricately linked to the ion channels on the neurons. The small and medium-sized DRG neurons are chiefly engaged in pain conduction and have high levels of TTX-S sodium channels, with Nav1.7 accounting for approximately 80% of the current. Voltage-gated sodium channel (VGSC or Nav) blockers are vital targets for the management of central nervous system diseases, particularly chronic pain. VGSCs play a key role in controlling cellular excitability. Clinical research has shown that Nav1.7 plays a crucial role in pain sensation, and there is strong genetic evidence linking Nav1.7 and its encoding gene SCN9A gene to painful disorders in humans. Many studies have shown that Nav1.7 plays an important role in pain management. The role of Nav1.7 in pain signaling pathways makes it an attractive target for the potential development of new pain drugs. Meanwhile, understanding the architecture of Nav1.7 may help to develop the next generation of painkillers. This review provides updates on the recently reported molecular inhibitors targeting the Nav1.7 pathway, summarizes their structure-activity relationships (SARs), and discusses their therapeutic effects on painful diseases. Pharmaceutical chemists are working to improve the therapeutic index of Nav1.7 inhibitors, achieve better analgesic effects, and reduce side effects. We hope that this review will contribute to the development of novel Nav1.7 inhibitors as potential drugs.
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Canal de Sodio Activado por Voltaje NAV1.7 , Bloqueadores del Canal de Sodio Activado por Voltaje , Humanos , Canal de Sodio Activado por Voltaje NAV1.7/metabolismo , Bloqueadores del Canal de Sodio Activado por Voltaje/farmacología , Bloqueadores del Canal de Sodio Activado por Voltaje/química , Bloqueadores del Canal de Sodio Activado por Voltaje/uso terapéutico , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Bibliotecas de Moléculas Pequeñas/uso terapéutico , Dolor en Cáncer/tratamiento farmacológico , Dolor en Cáncer/metabolismo , Analgésicos/química , Analgésicos/farmacología , Analgésicos/uso terapéutico , Animales , Relación Estructura-Actividad , Manejo del Dolor/métodos , Estructura Molecular , Neoplasias/tratamiento farmacológico , Bloqueadores de los Canales de Sodio/farmacología , Bloqueadores de los Canales de Sodio/química , Bloqueadores de los Canales de Sodio/uso terapéuticoRESUMEN
The presence of phenazopyridine in water is an environmental problem that can cause damage to human health and the environment. However, few studies have reported the adsorption of this emerging contaminant from aqueous matrices. Furthermore, existing research explored only conventional modeling to describe the adsorption phenomenon without understanding the behavior at the molecular level. Herein, the statistical physical modeling of phenazopyridine adsorption into graphene oxide is reported. Steric, energetic, and thermodynamic interpretations were used to describe the phenomenon that controls drug adsorption. The equilibrium data were fitted by mono, double, and multi-layer models, considering factors such as the numbers of phenazopyridine molecules by adsorption sites, density of receptor sites, and half saturation concentration. Furthermore, the statistical physical approach also calculated the thermodynamic parameters (free enthalpy, internal energy, Gibbs free energy, and entropy). The maximum adsorption capacity at the equilibrium was reached at 298 K (510.94 mg g-1). The results showed the physical meaning of adsorption, indicating that the adsorption occurs in multiple layers. The temperature affected the density of receptor sites and half saturation concentration. At the same time, the adsorbed species assumes different positions on the adsorbent surface as a function of the increase in the temperature. Meanwhile, the thermodynamic functions revealed increased entropy with the temperature and the equilibrium concentration.
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Nanoestructuras , Termodinámica , Adsorción , Nanoestructuras/química , Analgésicos/química , Grafito/química , Contaminantes Químicos del Agua/química , Carbono/químicaRESUMEN
Multitarget strategies are essential in addressing complex diseases, yet developing multitarget-directed ligands (MTDLs) is particularly challenging when aiming to engage multiple therapeutic targets across different tissues. Here, we present a molecular transformer strategy, enhancing traditional MTDLs. By utilizing esterase-driven hydrolysis, this approach mimics the adaptive nature of transformers for enabling molecules to modify their pharmacological effects in response to the biological milieu. By virtual screening and biological evaluation, we identified KGP-25, a novel compound initially targeting the voltage-gated sodium channel 1.8 (Nav1.8) in the peripheral nervous system (PNS) for analgesia, and later the γ-aminobutyric acid subtype A receptor (GABAA) in the central nervous system (CNS) for general anesthesia. Our findings confirm KGP-25's dual efficacy in cellular and animal models, effectively reducing opioid-related side effects. This study validates the molecular transformer approach in drug design and highlights its potential to overcome the limitations of conventional MTDLs, paving new avenues in innovative therapeutic strategies.
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Analgésicos , Esterasas , Ligandos , Analgésicos/farmacología , Analgésicos/química , Animales , Humanos , Esterasas/metabolismo , Anestésicos/farmacología , Anestésicos/química , Receptores de GABA-A/metabolismo , Receptores de GABA-A/química , Diseño de Fármacos , Ratones , MasculinoRESUMEN
Four new phenols and one new aminobenzoic acid derivative, with five known phenols were isolated from the roots of Rhus chinensis Mill. Their structures were elucidated by UV, IR, HRESIMS, 1D and 2D NMR spectra, as well as optical rotations. Compound 4 significantly inhibited mouse ear inflammation (inhibitory rate of 44.03%), and significantly extended the time of pain response (extension rate of 48.55%), showing significant anti-inflammatory and analgesic effects in vivo.