RESUMEN
Natural product celastrol is known to have various biological activities, yet its molecular targets that correspond to many activities remain unclear. Here, we used multiple mass-spectrometry-based approaches to identify catechol-O-methyltransferase (COMT) as a major binding target of celastrol and characterized their interaction comprehensively. Celastrol was found to inhibit the enzymatic activity of COMT and increased the dopamine level in neuroendocrine chromaffin cells significantly. Our study not only revealed a novel binding target of celastrol but also provided a new scaffold and cysteine hot spot for developing new generation COMT inhibitors in combating neurological disorders.
Asunto(s)
Inhibidores de Catecol O-Metiltransferasa , Triterpenos Pentacíclicos , Catecol O-Metiltransferasa/química , Inhibidores de Catecol O-Metiltransferasa/química , Inhibidores de Catecol O-Metiltransferasa/metabolismo , Inhibidores de Catecol O-Metiltransferasa/farmacología , Espectrometría de MasasRESUMEN
BACKGROUND: Parkinson's disease (PD) is the second most frequent neurodegenerative disease, which creates a significant public health burden. There is a challenge for the optimization of therapies since patients not only respond differently to current treatment options but also develop different side effects to the treatment. Genetic variability in the human genome can serve as a biomarker for the metabolism, availability of drugs and stratification of patients for suitable therapies. The goal of this systematic review is to assess the current evidence for the clinical translation of pharmacogenomics in the personalization of treatment for Parkinson's disease. METHODS: We performed a systematic search of Medline database for publications covering the topic of pharmacogenomics and genotype specific mutations in Parkinson's disease treatment, along with a manual search, and finally included a total of 116 publications in the review. RESULTS: We analyzed 75 studies and 41 reviews published up to December of 2020. Most research is focused on levodopa pharmacogenomic properties and catechol-O-methyltransferase (COMT) enzymatic pathway polymorphisms, which have potential for clinical implementation due to changes in treatment response and side-effects. Likewise, there is some consistent evidence in the heritability of impulse control disorder via Opioid Receptor Kappa 1 (OPRK1), 5-Hydroxytryptamine Receptor 2A (HTR2a) and Dopa decarboxylase (DDC) genotypes, and hyperhomocysteinemia via the Methylenetetrahydrofolate reductase (MTHFR) gene. On the other hand, many available studies vary in design and methodology and lack in sample size, leading to inconsistent findings. CONCLUSIONS: This systematic review demonstrated that the evidence for implementation of pharmacogenomics in clinical practice is still lacking and that further research needs to be done to enable a more personalized approach to therapy for each patient.
Asunto(s)
Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/genética , Antiparkinsonianos/efectos adversos , Antiparkinsonianos/metabolismo , Antiparkinsonianos/farmacología , Catecol O-Metiltransferasa/genética , Catecol O-Metiltransferasa/metabolismo , Inhibidores de Catecol O-Metiltransferasa/metabolismo , Inhibidores de Catecol O-Metiltransferasa/farmacología , Agonistas de Dopamina/metabolismo , Agonistas de Dopamina/farmacología , Genotipo , Humanos , Levodopa/efectos adversos , Levodopa/metabolismo , Levodopa/farmacología , Inhibidores de la Monoaminooxidasa/metabolismo , Inhibidores de la Monoaminooxidasa/farmacología , Enfermedad de Parkinson/metabolismo , Farmacogenética/métodos , Farmacogenética/tendencias , Variantes Farmacogenómicas , Investigación Biomédica TraslacionalAsunto(s)
Antiparkinsonianos/uso terapéutico , Inhibidores de Catecol O-Metiltransferasa/uso terapéutico , Catecol O-Metiltransferasa , Oxadiazoles/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Antiparkinsonianos/metabolismo , Catecol O-Metiltransferasa/metabolismo , Inhibidores de Catecol O-Metiltransferasa/metabolismo , Ensayos Clínicos como Asunto/métodos , Humanos , Oxadiazoles/metabolismo , Enfermedad de Parkinson/metabolismoRESUMEN
BACKGROUND: The most effective symptomatic treatment of Parkinson's disease remains the metabolic precursor of dopamine, L-dopa. To enhance the efficacy of L-dopa, it is often combined with inhibitors of the enzymes, catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO) B, key metabolic enzymes of L-dopa and dopamine. OBJECTIVE: This study attempted to discover compounds that exhibit dual inhibition of COMT and MAO-B among a library of 40 structurally diverse natural compounds. Such dual acting inhibitors may be effective as adjuncts to L-dopa and offer enhanced value in the management of Parkinson's disease. METHODS: Selected natural compounds were evaluated as in vitro inhibitors of rat liver COMT and recombinant human MAO. Reversibility of MAO inhibition was investigated by dialysis. RESULTS: Among the natural compounds morin (IC50 = 1.32 µM), chlorogenic acid (IC50 = 6.17 µM), (+)-catechin (IC50 = 0.86 µM), alizarin (IC50 = 0.88 µM), fisetin (IC50 = 5.78 µM) and rutin (IC50 = 25.3 µM) exhibited COMT inhibition. Among these active COMT inhibitors only morin (IC50 = 16.2 µM), alizarin (IC50 = 8.16 µM) and fisetin (IC50 = 7.33 µM) were noteworthy MAO inhibitors, with specificity for MAO-A. CONCLUSION: None of the natural products investigated here are dual COMT/MAO-B inhibitors. However, good potency COMT inhibitors have been identified, which may serve as leads for future development of COMT inhibitors.
Asunto(s)
Productos Biológicos/farmacología , Inhibidores de Catecol O-Metiltransferasa/metabolismo , Catecol O-Metiltransferasa/farmacología , Inhibidores de la Monoaminooxidasa/farmacología , Monoaminooxidasa/metabolismo , Animales , Antraquinonas/química , Antraquinonas/farmacología , Antioxidantes/química , Antioxidantes/farmacología , Productos Biológicos/química , Catecol O-Metiltransferasa/química , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Flavonoides/química , Flavonoides/farmacología , Flavonoles , Humanos , Hígado/efectos de los fármacos , Hígado/enzimología , Inhibidores de la Monoaminooxidasa/química , Ratas , Ratas Sprague-DawleyRESUMEN
The metabolism of the masking agent tolcapone in the horse has been investigated. This substance was found to have undergone various chemical transformations that produced a large variety of phase I metabolites, as well as glucuronide and sulfate conjugation. Confirmation of the presence of tolcapone and the 3-O-methylated metabolite in the blood samples collected up to 240 minutes and in urine obtained up to 24 hours, was successfully conducted using both gas chromatography- and liquid chromatography-tandem mass spectrometry techniques. The 3-O-methyl tolcapone is the better marker to use in a screening method because, in comparison to tolcapone, we have found that this substance offers superior chromatographic performance that should potentially give a lower limit of detection.
Asunto(s)
Inhibidores de Catecol O-Metiltransferasa/sangre , Inhibidores de Catecol O-Metiltransferasa/orina , Caballos/sangre , Caballos/orina , Tolcapona/sangre , Tolcapona/orina , Animales , Inhibidores de Catecol O-Metiltransferasa/metabolismo , Cromatografía Líquida de Alta Presión , Monitoreo de Drogas , Cromatografía de Gases y Espectrometría de Masas , Caballos/metabolismo , Metilación , Detección de Abuso de Sustancias , Tolcapona/metabolismoRESUMEN
A series of 8-hydroxy quinolines were identified as potent inhibitors of catechol O-methyltransferase (COMT) with selectivity for the membrane-bound form of the enzyme. Small substituents at the 7-position of the quinoline were found to increase metabolic stability without sacrificing potency. Compounds with good pharmacokinetics and brain penetration were identified and demonstrated in vivo modulation of dopamine metabolites in the brain. An X-ray cocrystal structure of compound 21 in the S-COMT active site shows chelation of the active site magnesium similar to catechol-based inhibitors. These compounds should prove useful for treatment of many neurological and psychiatric conditions associated with compromised cortical dopamine signaling.
Asunto(s)
Inhibidores de Catecol O-Metiltransferasa/química , Inhibidores de Catecol O-Metiltransferasa/farmacología , Catecol O-Metiltransferasa/metabolismo , Diseño de Fármacos , Oxiquinolina/química , Oxiquinolina/farmacología , Animales , Encéfalo/metabolismo , Catecol O-Metiltransferasa/química , Inhibidores de Catecol O-Metiltransferasa/metabolismo , Inhibidores de Catecol O-Metiltransferasa/farmacocinética , Masculino , Ratones , Modelos Moleculares , Oxiquinolina/metabolismo , Oxiquinolina/farmacocinética , Conformación Proteica , Ratas , Distribución TisularRESUMEN
Functional pain syndromes, such as fibromyalgia and temporomandibular disorder, are associated with enhanced catecholamine tone and decreased levels of catechol-O-methyltransferase (COMT; an enzyme that metabolizes catecholamines). Consistent with clinical syndromes, our lab has shown that sustained 14-day delivery of the COMT inhibitor OR486 in rodents results in pain at multiple body sites and pain-related volitional behaviors. The onset of COMT-dependent functional pain is mediated by peripheral ß2- and ß3-adrenergic receptors (ß2- and ß3ARs) through the release of the pro-inflammatory cytokines tumor necrosis factor α (TNFα), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6). Here, we first sought to investigate the role of ß2- and ß3ARs and downstream mediators in the maintenance of persistent functional pain. We then aimed to characterize the resulting persistent inflammation in neural tissues (neuroinflammation), characterized by activated glial cells and phosphorylation of the mitogen-activated protein kinases (MAPKs) p38 and extracellular signal-regulated kinase (ERK). Separate groups of rats were implanted with subcutaneous osmotic mini-pumps to deliver OR486 (15â¯mg/kg/day) or vehicle for 14â¯days. The ß2AR antagonist ICI118551 and ß3AR antagonist SR59230A were co-administrated subcutaneously with OR486 or vehicle either on day 0 or day 7. The TNFα inhibitor Etanercept, the p38 inhibitor SB203580, or the ERK inhibitor U0126 were delivered intrathecally following OR486 cessation on day 14. Behavioral responses, pro-inflammatory cytokine levels, glial cell activation, and MAPK phosphorylation were measured over the course of 35â¯days. Our results demonstrate that systemic delivery of OR486 leads to mechanical hypersensitivity that persists for at least 3â¯weeks after OR486 cessation. Corresponding increases in spinal TNFα, IL-1ß, and IL-6 levels, microglia and astrocyte activation, and neuronal p38 and ERK phosphorylation were observed on days 14-35. Persistent functional pain was alleviated by systemic delivery of ICI118551 and SR59230A beginning on day 0, but not day 7, and by spinal delivery of Etanercept or SB203580 beginning on day 14. These results suggest that peripheral ß2- and ß3ARs drive persistent COMT-dependent functional pain via increased activation of immune cells and production of pro-inflammatory cytokines, which promote neuroinflammation and nociceptor activation. Thus, therapies that resolve neuroinflammation may prove useful in the management of functional pain syndromes.
Asunto(s)
Dolor/metabolismo , Receptores Adrenérgicos beta 2/efectos de los fármacos , Receptores Adrenérgicos beta 2/metabolismo , Receptores Adrenérgicos beta 3/metabolismo , Animales , Catecol O-Metiltransferasa/metabolismo , Inhibidores de Catecol O-Metiltransferasa/metabolismo , Catecoles/farmacología , Citocinas/metabolismo , Etanercept/farmacología , Femenino , Fibromialgia/metabolismo , Fibromialgia/fisiopatología , Hiperalgesia/metabolismo , Imidazoles/farmacología , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Masculino , Microglía/metabolismo , Proteínas Quinasas Activadas por Mitógenos , Neuroglía/metabolismo , Dolor/fisiopatología , Fosforilación , Propanolaminas/farmacología , Piridinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptores Adrenérgicos beta/metabolismo , Receptores Adrenérgicos beta 2/fisiología , Receptores Adrenérgicos beta 3/efectos de los fármacos , Receptores Adrenérgicos beta 3/fisiología , Médula Espinal/metabolismo , Trastornos de la Articulación Temporomandibular/metabolismo , Trastornos de la Articulación Temporomandibular/fisiopatología , Factor de Necrosis Tumoral alfa/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
In this work, voltammetric data recorded at a glassy carbon electrode (GCE) were separately used to investigate the interactions of entacapone (Comtan, CAT) with human serum albumin (HSA). Then, an augmented data matrix was constructed by the combination of voltammetric and spectroscopic data and simultaneously analysed by multivariate curve resolution-alternating least squares (MCR-ALS) to obtain more information about CAT-HSA interactions. The absence of rotational ambiguities in results obtained by MCR-ALS was verified with the help of MCR-BANDS and we confirmed that the results were unambiguous and reliable. Binding of CAT to HSA was also modeled by molecular docking and the results were compatible with those of obtained by recording experimental data. Hard-modeling of combined voltammetric and spectroscopic data by EQUISPEC as an efficient chemometric algorithm helped us to compute binding constant of CAT-HSA complex specie which was in a good agreement with the binding constant value obtained by direct analysis of experimental data. For electrochemical sensing of serum albumin two amperometric measurements were performed to determine HSA in 2-27â¯nM and 27-70â¯nM with a limit of detection of 0.51â¯nM and a sensitivity of 1.84⯵Aâ¯nM-1.
Asunto(s)
Antiparkinsonianos/metabolismo , Inhibidores de Catecol O-Metiltransferasa/metabolismo , Catecoles/metabolismo , Nitrilos/metabolismo , Albúmina Sérica Humana/metabolismo , Técnicas Biosensibles , Técnicas Electroquímicas , Humanos , Simulación del Acoplamiento Molecular , Unión Proteica , Albúmina Sérica Humana/análisis , Espectrometría de Fluorescencia , Espectrofotometría UltravioletaRESUMEN
1. Finding and developing inhibitors of catechol-O-methyltransferase (COMT) from natural products is highly recommended. Daphnetin, a naturally occurring catechol from the family thymelaeaceae, has a chemical structure similar to several potent COMT inhibitors reported previously. Here the potential of daphnetin and its Phase II metabolites as inhibitors of COMT was investigated with human liver cytosol (HLC). 2. Daphnetin and its methylated metabolite (8-O-methyldaphnetin) were found to inhibit COMT-mediated dopamine O-methylation in a dose-dependent manner. The IC50 values for daphnetin (0.51â¼0.53 µM) and 8-O-methyldaphnetin (22.5â¼24.3 µM) were little affected by changes in HLC concentrations. Further kinetic analysis showed the differences in inhibition type and parameters (Ki) between daphnetin (competitive, 0.37 µM) and 8-O-methyldaphnetin (noncompetitive, 25.7 µM). Other metabolites, including glucuronidated and sulfated species, showed negligible inhibition against COMT. By using in vitro-in vivo extrapolation (IV-IVE), a 24.3-fold increase in the exposure of the COMT substrates was predicted when they are co-administrated with daphnetin. 3. With high COMT-inhibiting activity, daphnetin could serve as a lead compound for the design and development of new COMT inhibitors. Also, much attention should be paid to the clinical impact of combination of daphnetin and herbal preparations containing daphnetin with the drugs primarily cleared by COMT.
Asunto(s)
Inhibidores de Catecol O-Metiltransferasa/farmacología , Catecol O-Metiltransferasa/metabolismo , Umbeliferonas/farmacología , Inhibidores de Catecol O-Metiltransferasa/metabolismo , Dopamina , Inhibidores Enzimáticos/farmacología , Humanos , Cinética , Fase II de la Desintoxicación Metabólica , Metilación , Umbeliferonas/metabolismoRESUMEN
Oral opicapone (Ongentys(®)), a potent, third-generation, long-acting, peripheral catechol-O-methyltransferase (COMT) inhibitor, is approved as adjunctive treatment to levodopa (L-Dopa)/dopa-decarboxylase inhibitor (DDCI) therapy in adults with Parkinson's disease (PD) and end-of-dose motor fluctuations who cannot be stabilized on those combinations. In 14- to 15-week, double-blind, multinational trials and in 1-year, open-label extension studies in this patient population, opicapone was an effective and generally well tolerated adjunctive therapy to L-Dopa plus a DDCI and other PD therapy. During the double-blind phase, adjunctive opicapone 50 mg once daily provided significantly greater improvements in motor fluctuations than placebo, with these improvements noninferior to those with entacapone. These beneficial improvements in motor fluctuations with opicapone were maintained in patients who continued adjunctive opicapone during the extension studies, with patients who switched from placebo or entacapone to opicapone experiencing significant improvements in motor fluctuations during this year. No new unexpected safety concerns were identified after ≈1.4 years' treatment with opicapone, with no serious cases of hepatotoxicity reported in clinical trials. With its convenient once-daily regimen, oral opicapone is an emerging COMT inhibitor option for use as adjunctive therapy to L-Dopa/DDCI therapy in adults with PD and end-of dose motor fluctuations who cannot be stabilized on those combinations.
Asunto(s)
Antiparkinsonianos/uso terapéutico , Oxadiazoles/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Inhibidores de Descarboxilasas de Aminoácidos Aromáticos/administración & dosificación , Inhibidores de Descarboxilasas de Aminoácidos Aromáticos/metabolismo , Inhibidores de Descarboxilasas de Aminoácidos Aromáticos/farmacocinética , Inhibidores de Descarboxilasas de Aminoácidos Aromáticos/uso terapéutico , Inhibidores de Catecol O-Metiltransferasa/administración & dosificación , Inhibidores de Catecol O-Metiltransferasa/metabolismo , Inhibidores de Catecol O-Metiltransferasa/farmacocinética , Inhibidores de Catecol O-Metiltransferasa/uso terapéutico , Método Doble Ciego , Interacciones Farmacológicas , Quimioterapia Combinada , Humanos , Levodopa/administración & dosificación , Levodopa/metabolismo , Levodopa/farmacocinética , Levodopa/uso terapéutico , Persona de Mediana Edad , Oxadiazoles/administración & dosificación , Oxadiazoles/metabolismo , Oxadiazoles/farmacocinéticaRESUMEN
Entacapone is an inhibitor of catechol-O-methyltransferase (COMT) and is being used to extend the therapeutic effect of levodopa in patients with advanced and fluctuating Parkinson's disease. Entacapone has low and variable oral bioavailability and the underlying mechanism(s) for this behavior have not been studied. To explain such behavior and to characterize the dynamic changes in the metabolism of entacapone, a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model was developed integrating in silico, in vitro and in vivo pharmacokinetic data. The model was developed and verified in healthy volunteers and subsequently expanded to predict the pharmacokinetic parameters of entacapone phosphate, a prodrug of entacapone, and to assess the impact of hepatic impairment on the pharmacokinetics of entacapone. Low and inter-individual variability in bioavailability could be attributed to the extensive first-pass metabolism by UGTs in the liver and, to a lesser extent, the small intestine. The predictive performance of this model was acceptable with predicted Cmax , AUC and PD parameters lying within 20% of the observed data. The model indicates that the low bioavailability could be attributed to the extensive first-pass effect of entacapone.
Asunto(s)
Antiparkinsonianos/farmacocinética , Inhibidores de Catecol O-Metiltransferasa/farmacocinética , Catecoles/farmacocinética , Absorción Intestinal , Hígado/metabolismo , Modelos Biológicos , Nitrilos/farmacocinética , Profármacos/farmacocinética , Adulto , Animales , Antiparkinsonianos/sangre , Antiparkinsonianos/química , Antiparkinsonianos/metabolismo , Disponibilidad Biológica , Biotransformación , Células CACO-2 , Inhibidores de Catecol O-Metiltransferasa/sangre , Inhibidores de Catecol O-Metiltransferasa/química , Inhibidores de Catecol O-Metiltransferasa/metabolismo , Catecoles/sangre , Catecoles/química , Catecoles/metabolismo , Biología Computacional , Enterocitos/metabolismo , Sistemas Especialistas , Humanos , Masculino , Tasa de Depuración Metabólica , Nitrilos/sangre , Nitrilos/química , Nitrilos/metabolismo , Fosforilación , Profármacos/análisis , Profármacos/química , Profármacos/metabolismo , Ratas , Solubilidad , Distribución TisularRESUMEN
1. The aim of this study was to investigate the biotransformation of salvianolic acid B (SAB) by catechol-O-methyltransferase (COMT) and its interaction with levodopa (l-DOPA) methylation in rats. 2. The enzyme kinetics of SAB were studied after incubation with rat COMT. The in vivo SAB and 3-monomethyl-SAB (3-MMS) levels were determined after a single dose of tolcapone with or without SAB administration. For l-DOPA, the effect of SAB inhibition on l-DOPA methylation was studied in vitro. The l-DOPA and 3-O-methyldopa (3-OMD) levels were determined after single and multiple doses of SAB with or without l-DOPA administration. 3. After incubation, we found that SAB was methylated mainly by rat liver and kidney COMT. Tolcapone strongly inhibited the formation of 3-MMS in vitro and in vivo, without any change in the plasma concentration of SAB. Moreover, tolcapone significantly increased the cumulative bile excretion of SAB from 3% to 40% in the rat. SAB inhibited the methylation of l-DOPA with an IC50 value of 2.08 µM in vitro. In vivo, a single intravenous dose of SAB decreased the plasma concentration of 3-OMD, with no obvious effect on the pharmacokinetics of l-DOPA. Multiple doses of SAB given to rats also decreased the plasma concentration of 3-OMD, while SAB increased the plasma concentration of l-DOPA.