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Several rare neurodegenerative diseases, including chorea acanthocytosis, are caused by mutations in the VPS13A&ndash, D genes. Only symptomatic treatments for these diseases are available. Saccharomyces cerevisiae contains a unique VPS13 gene and the yeast vps13&Delta, mutant has been proven as a suitable model for drug tests. A library of drugs and an in-house library of natural compounds and their derivatives were screened for molecules preventing the growth defect of vps13&Delta, cells on medium with sodium dodecyl sulfate (SDS). Seven polyphenols, including the iron-binding flavone luteolin, were identified. The structure&ndash, activity relationship and molecular mechanisms underlying the action of luteolin were characterized. The FET4 gene, which encodes an iron transporter, was found to be a multicopy suppressor of vps13&Delta, pointing out the importance of iron in response to SDS stress. The growth defect of vps13&Delta, in SDS-supplemented medium was also alleviated by the addition of iron salts. Suppression did not involve cell antioxidant responses, as chemical antioxidants were not active. Our findings support that luteolin and iron may target the same cellular process, possibly the synthesis of sphingolipids. Unveiling the mechanisms of action of chemical and genetic suppressors of vps13&Delta, may help to better understand VPS13A&ndash, D-dependent pathogenesis and to develop novel therapeutic strategies.

Gambling disorder is a behavioral addiction associated with impairments in value-based decision-making and cognitive control. These functions are thought to be regulated by dopamine within fronto-striatal circuits, but the role of altered dopamine neurotransmission in the etiology of gambling disorder remains controversial. Preliminary evidence suggests that increasing frontal dopamine tone might improve cognitive functioning in gambling disorder. We therefore examined whether increasing frontal dopamine tone via a single dose of the catechol-O-methyltransferase (COMT) inhibitor tolcapone would reduce risky choice in human gamblers (n=14) in a randomized double-blind placebo-controlled crossover study. Data were analyzed using hierarchical Bayesian parameter estimation and a combined risky choice drift diffusion model. Model comparison revealed a non-linear mapping from value differences to trial-wise drift rates, confirming recent findings. An increase in risk-taking under tolcapone vs. placebo was about five times more likely, given the data, than a decrease (BF = 0.2). Examination of drug effects on diffusion model parameters revealed that an increase in the value-dependency of the drift rate under tolcapone was about thirteen times more likely than a decrease (BF = .073). In contrast, a reduction in the maximum drift rate under tolcapone was about seven times more likely than an increase (BF = 7.51). Results add to previous work on COMT inhibitors in behavioral addictions and to mounting evidence for the applicability of diffusion models in value-based decision-making. Future work should focus on individual genetic, clinical and cognitive factors that might account for heterogeneity in the effects of COMT inhibition. Significance statement Gambling disorder is associated with impairments in value-based decision-making and cognitive control, functions regulated by the neurotransmitter dopamine. Here we examined whether increasing frontal dopamine tone via the catechol-O-methyltransferase (COMT) inhibitor tolcapone would reduce risky choice in a group of gamblers. Computational modeling did not reveal consistent reductions in risky decision-making under tolcapone in gamblers. If anything, tolcapone increased risky choice. Future work should focus on individual genetic, clinical and cognitive factors that might account for heterogeneity in the effects of COMT inhibition.

The last couple of months have witnessed the world in a state of virtual standstill. The SARS-CoV-2 virus has overtaken the globe to economic and social lockdown. Many patients with COVID-19 have compromised immunity, especially in an aged population suffering from Parkinson's disease (PD). : Alteration in dopaminergic neurons and deficiency of dopamine in PD patients are the most common symptoms affecting 1% population above the age of 60 years. The compromised immune system and inflammatory manifestation in PD patients make them an easy target. The most common drugs under trial for COVID-19 are remdesivir, favipiravir, chloroquine and hydroxychloroquine, azithromycin along with adjunct drugs like amantadine with some monoclonal antibodies. : Presently, clinically US FDA approved drugs in PD include Levodopa, catechol-O-methyl transferase (COMT) inhibitors, (Entacapone and Tolcapone), dopamine agonists (Bromocriptine, Ropinirole, Pramipexole, and Rotigotine), monoamine oxidase B (MAO-B) inhibitors (Selegiline and Rasagiline), amantadine and antimuscarinic drugs. The drugs have established mechanisms of action on PD patients with known pharmacodynamics and pharmacokinetic properties along with dose and adverse effects. : Conclusion and relevance of this review focus on the drugs that can be tried on PD patients with SAR CoV-2 infection, in particular, amantadine that has been approved by all the developed countries as a common drug possessing both antiviral properties by downregulation of CTSL, lysosomal pathway disturbance and change in pH necessary to uncoat the viral proteins and anti- Parkinson properties. To deal with the significant prognostic adverse effect of SARS-CoV-2 on PD, the present-day treatment options, clinical presentation and various mechanisms are the need of the hour.

RATIONALE: Cognitive impairment is a primary feature of many neuropsychiatric disorders and there is a need for new therapeutic options. Catechol-O-methyltransferase (COMT) inhibitors modulate cortical dopaminergic function and have been proposed as potential cognitive enhancers. Unfortunately, currently available COMT inhibitors are not good candidates due to either poor blood-brain barrier penetration or severe toxicity. OBJECTIVES: To address the need for safe, brain-penetrant COMT inhibitors, we tested multiple novel compounds in a set of preclinical in vivo efficacy assays in rats to determine their ability to inhibit COMT function and viability as potential clinical candidates. METHODS: We measured the change in concentration of dopamine (DA) metabolites in cerebrospinal fluid (CSF) from the cisterna magna and extracellular fluid (ECF) from the frontal cortex produced by our novel compounds. Additionally, we tested the effects of our brain-penetrant COMT inhibitors in an attentional set-shifting assay (ASST). We benchmarked the performance of the novel COMT inhibitors to the effects produced by the known COMT inhibitor tolcapone. RESULTS: We found that multiple COMT inhibitors, exemplified by LIBD-1 and LIBD-3, significantly modulated dopaminergic function measured as decreases in homovanillic acid (HVA) and increases in 3,4-Dihydroxyphenylacetic acid (DOPAC), two DA metabolites, in CSF and the frontal cortex. Additionally, we found the LIBD-1 significantly improved cognitive flexibility in the ASST, an effect previously reported following tolcapone administration. CONCLUSIONS: These results demonstrate that LIBD-1 is a novel COMT inhibitor with promising in vivo activity and the potential to serve as a new therapy for cognitive impairment.

Introduction: Opicapone (OPC) is a well-established catechol-O-methyltransferase (COMT) inhibitor that is approved for the treatment of Parkinson's disease (PD) associated with L-DOPA / L-amino acid decarboxylase inhibitor (DDI) therapy allowing for prolonged activity due to a more continuous supply of L-DOPA in the brain. Thus, OPC decreases fluctuation in L-DOPA plasma levels and favours more constant central dopaminergic receptor stimulation, thus improving PD symptomatology. Areas covered: This review evaluates the preclinical development, pharmacology, pharmacokinetics and safety profile of OPC. Data were extracted from published preclinical and clinical studies published on PUBMED and SCOPUS (Search period: 2000-2019). Clinical and post-marketing data were also evaluated. Expert opinion: OPC is a third generation COMT inhibitor with a novel structure. It has an efficacy and tolerability superior to its predecessors, tolcapone (TOL) and entacapone (ENT). It also provides a safe and simplified drug regimen that allows neurologists to individually adjust the existing daily administration of L-DOPA. OPC is indicated as an adjunctive therapy to L-DOPA/DDI in patients with PD and end-of-dose motor fluctuations who cannot be stabilised on those combinations. Abbreviations: 3-OMD, 3-O-methyldopa; 6-OHDA, 6-hydroxydopamine; BG, basal ganglia; COMT, Catechol-O-methyltransferase; DDI, decarboxylase inhibitors; ENT, Entacapone; FDA, Food and Drug Administration; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; OPC, Opicapone; PD, Parkinson's disease; TOL, Tolcapone; GDNF, Glial cell-line-derived neurotrophic factor; NTN, neurturin; ICV, Intracerebroventricular; PDUFA, Prescription Drug User Fees Act; EMA, European Medicine Administration; AE, Adverse event BG, Basal ganglia. QD, once a day.

Catechol O-methyltransferase (COMT) inhibitors are valuable co-adjuvant drugs in the clinical management of Parkinson's disease (PD), and recent data also suggest therapeutic benefits in other neurological disorders associated with dopamine depletion. However, the relationship between tolcapone administration with fatal cases of drug-induced liver damage gave COMT inhibitors a bad reputation as hepatotoxic drugs. Thus, there is a pressing need to feed the pipeline with safe COMT inhibitors to replace tolcapone, the only currently available COMT inhibitor that effectively reaches the brain. Recent efforts led to promising phenolic and nonphenolic COMT inhibitors, which allow isoform-specific targeting and avoid the toxicological and pharmacokinetic (PK) shortcomings of classic nitrocatechols. Here, we describe advances made in this field over the past 5 years.

BACKGROUND: There are currently no disease-targeted treatments for cognitive or behavioral symptoms in patients with behavioral variant frontotemporal dementia (bvFTD). OBJECTIVE: To determine the effect of tolcapone, a specific inhibitor of Catechol-O-Methyltransferase (COMT), in patients with bvFTD. METHODS: In this randomized, double-blind, placebo-controlled, cross-over study at two study sites, we examined the effect of tolcapone on 28 adult outpatients with bvFTD. The primary outcome was reaction time on the N-back cognitive test. As an imaging outcome, we examined differences in the resting blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) signal intensity between subjects on placebo versus tolcapone performing the N-back test. Secondary outcomes included measures of cognitive performance and behavioral disturbance using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Neuropsychiatric Inventory-Questionnaire (NPI-Q), and Clinical Global Impressions scale (CGI). RESULTS: Tolcapone was well tolerated and no patients dropped out. The most frequent treatment-related adverse event during tolcapone treatment was elevated liver enzymes (21%). There were no significant differences between tolcapone treatment and placebo in the primary or imaging outcomes. However, there were significant differences between RBANS total scores (p < 0.01), NPI-Q total scores (p = 0.04), and CGI total scores (p = 0.035) between treatment conditions which were driven by differences between baseline and tolcapone conditions. Further, there was a trend toward significance between tolcapone and placebo on the CGI (p = 0.078). CONCLUSIONS: Further study of COMT inhibition and related approaches with longer duration of treatment and larger sample sizes in frontotemporal lobar degeneration-spectrum disorders may be warranted.

RationaleIndividuals suffering from alcohol use disorder (AUD) demonstrate difficulty with decision-making and impulsivity that may be associated with impaired frontal cortical function. Therapeutics that enhance frontal dopamine tone could decrease impulsivity and in turn reduce alcohol consumption in individuals with AUD.ObjectivesTo determine if the catechol-O-methyltransferase (COMT) inhibitor tolcapone can attenuate alcohol consumption in individuals with AUD and whether this attenuation correlates with tolcapone-induced changes in laboratory-based decision-making tasks.MethodsWe used daily self-report and a novel group laboratory bar task to assess the effects of randomized double-blind crossover administration of tolcapone (100mg TID for 5days) on alcohol consumption and laboratory tasks assessing impulsivity in 55 non-treatment-seeking subjects with AUD.ResultsTolcapone significantly reduced self-reported alcohol consumption (t (54) = 2.05, p = 0.045). The effects of tolcapone on drinking significantly correlated with changes in impulsive decision-making, such that subjects with the greatest decrease in impulsive choice on tolcapone also reported the greatest decrease in alcohol consumption (r (45) = 0.40, p = 0.0053). We did not see effects of tolcapone on laboratory bar consumption. Adverse event (AE) reporting was low, with no significant difference in frequency or severity of AEs on tolcapone versus placebo.ConclusionsThese data demonstrate that COMT inhibitors such as tolcapone may be useful therapeutics for AUD.Trial registrationClinicalTrials.gov Identifier: NCT02740582.

We have utilized multiparametric surface plasmon resonance and impendance-based quartz crystal microbalance instruments to study the distribution coefficients of catechol derivatives in cell model membranes. Our findings verify that the octanol-water partitioning coefficient is a poor descriptor of the total lipid affinity for small molecules which show limited lipophilicity in the octanol-water system. Notably, 3-methoxytyramine, the methylated derivative of the neurotransmitter dopamine, showed substantial affinity to the lipids despite its nonlipophilic nature predicted by octanol-water partitioning. The average ratio of distribution coefficients between 3-methoxytyramine and dopamine was 8.0. We also found that the interactions between the catechols and the membranes modeling the cell membrane outer leaflet are very weak, suggesting a mechanism other than the membrane-mediated mechanism of action for the neurotransmitters at the postsynaptic site. The average distribution coefficient for these membranes was one-third of the average value for pure phosphatidylcholine membranes, calculated using all compounds. In the context of our previous work, we further theorize that membrane-bound enzymes can utilize membrane headgroup partitioning to find their substrates. This could explain the differences in enzyme affinity between soluble and membrane-bound isoforms of catechol-O-methyltransferase, an essential enzyme in catechol metabolism.

Transthyretin (TTR) is an amyloidogenic homotetramer involved in the transport of thyroxine and retinol in blood and cerebrospinal fluid. TTR stabilizers, such as tolcapone, an FDA approved drug for Parkinson's disease, are able to interact with residues of the thyroxine-binding sites of TTR, both wild type and pathogenic mutant forms, thereby stabilizing its tetrameric native state and inhibiting amyloidogenesis. Herein, we report on the synthesis of 3-deoxytolcapone, a novel stabilizer of TTR. The high-resolution X-ray analyses of the interactions of 3-O-methyltolcapone and 3-deoxytolcapone with TTR were performed. In the two TTR-ligand complexes the tolcapone analogues establish mainly H-bond and hydrophobic interactions with residues of the thyroxine-binding site of the TTR tetramer. Both compounds are capable of high and selective stabilization of TTR in the presence of plasma proteins, despite their markedly different 'forward' and 'reverse' binding mode, respectively. In fact, the loss or the weakening of stabilizing interactions with protein residues of 3-deoxytolcapone in comparison with tolcapone and 3-O-methyltolcapone is compensated by new interactions established at the dimer-dimer interface. Our data, coupled with previously reported data on the pharmacokinetics properties in humans of tolcapone and 3-O-methyltolcapone, further support the relevance of the latter tolcapone analogue as TTR stabilizer.

15 pags., 9 figs., 3 tabs., Hereditary transthyretin amyloidosis (ATTR) is a disease characterized by the extracellular deposition of transthyretin (TTR) amyloid fibrils. Highly destabilizing TTR mutations cause leptomeningeal amyloidosis, a rare, but fatal, disorder in which TTR aggregates in the brain. The disease remains intractable, since liver transplantation, the reference therapy for systemic ATTR, does not stop mutant TTR production in the brain. In addition, despite current pharmacological strategies have shown to be effective against in vivo TTR aggregation by stabilizing the tetramer native structure and precluding its dissociation, they display low brain permeability. Recently, we have repurposed tolcapone as a molecule to treat systemic ATTR. Crystal structures and biophysical analysis converge to demonstrate that tolcapone binds with high affinity and specificity to three unstable leptomeningeal TTR variants, stabilizing them and, consequently, inhibiting their aggregation. Because tolcapone is an FDA-approved drug that crosses the blood-brain barrier, our results suggest that it can translate into a first disease-modifying therapy for leptomeningeal amyloidosis. DATABASES: PDB codes for A25T-TTR, V30G-TTR, and Y114C-TTR bound to tolcapone are 6TXV, 6TXW, and 6XTK, respectively., This work was funded by the Spanish Ministry of Economy and Competitiveness BIO2016-78310-R to SV and by ICREA, ICREA-Academia 2015, to SV

Effort-related choice (ERC) tasks allow animals to choose between high-value reinforcers that require high effort to obtain and low-value/low-effort reinforcers. Dopaminergic neuromodulation regulates ERC behavior. The enzyme catechol-O-methyltransferase (COMT) metabolizes synaptically-released dopamine. COMT is the predominant regulator of dopamine turnover in regions of the brain with low levels of dopamine transporters (DATs), including the prefrontal cortex (PFC). Here, we evaluated the effects of the COMT inhibitor tolcapone on ERC performance in a touchscreen-based fixed-ratio/concurrent chow task in male mice. In this task, mice were given the choice between engaging in a fixed number of instrumental responses to acquire a strawberry milk reward and consuming standard lab chow concurrently available on the chamber floor. We found no significant effects of tolcapone treatment on either strawberry milk earned or chow consumed compared to vehicle treatment. In contrast, we found that haloperidol decreased instrumental responding for strawberry milk and increased chow consumption as seen in previously published studies. These data suggest that COMT inhibition does not significantly affect effort-related decision making in a fixed-ratio/concurrent chow task in male mice.

Lewy body diseases such as Parkinson's disease involve intraneuronal deposition of the protein α-synuclein (AS) and depletion of nigrostriatal dopamine (DA). Interactions of AS with DA oxidation products may link these neurohistopathologic and neurochemical abnormalities via two potential pathways: spontaneous oxidation of DA to dopamine-quinone and enzymatic oxidation of DA catalyzed by monoamine oxidase to form 3,4-dihydroxyphenylacetaldehyde (DOPAL), which is then oxidized to DOPAL-Q. We compared these two pathways in terms of the ability of DA and DOPAL to modify AS. DOPAL was far more potent than DA both in oligomerizing and forming quinone-protein adducts with (quinonizing) AS. The DOPAL-induced protein modifications were enhanced similarly by pro-oxidation with Cu(II) or tyrosinase and inhibited similarly by antioxidation with N-acetylcysteine. Dopamine oxidation evoked by Cu(II) or tyrosinase did not quinonize AS. In cultured MO3.13 human oligodendrocytes DOPAL resulted in the formation of numerous intracellular quinoproteins that were visualized by near-infrared spectroscopy. We conclude that of the two routes by which oxidation of DA modifies AS and other proteins the route via DOPAL is more prominent. The results support developing experimental therapeutic strategies that might mitigate deleterious modifications of proteins such as AS in Lewy body diseases by targeting DOPAL formation and oxidation. SIGNIFICANCE STATEMENT: Interactions of the protein α-synuclein with products of dopamine oxidation in the neuronal cytoplasm may link two hallmark abnormalities of Parkinson disease: Lewy bodies (which contain abundant AS) and nigrostriatal DA depletion (which produces the characteristic movement disorder). Of the two potential routes by which DA oxidation may alter AS and other proteins, the route via the autotoxic catecholaldehyde 3,4-dihydroxyphenylacetaldehyde is more prominent; the results support experimental therapeutic strategies targeting DOPAL formation and DOPAL-induced protein modifications.

Effort-related choice (ERC) tasks allow animals to choose between high-value reinforcers that require high effort to obtain or low-value/low-effort reinforcers. Dopaminergic neuromodulation regulates effort-related choice behavior. The enzyme catechol-O-methyltransferase (COMT) metabolizes synaptically-released dopamine. COMT is the predominate regulator of dopamine turnover in regions of the brain with low levels of dopamine transporters, including the prefrontal cortex. Here, we evaluated the effects of the COMT inhibitor tolcapone on ERC performance in a touchscreen-based fixed-ratio/concurrent chow assay in male mice. In this task, mice were given the choice between engaging in a fixed number of instrumental responses to acquire a strawberry milk reward and consuming standard lab chow concurrently available on the chamber floor. We found no significant effects of tolcapone treatment on either strawberry milk earned or chow consumed compared to vehicle treatment. In contrast, we found that haloperidol decreased instrumental responding for strawberry milk and increased chow consumption as seen in previously published studies. These data suggest that COMT inhibition does not significantly affect effort-related decision making in a fixed-ratio/concurrent chow task in male mice.

Monitoring risk is often an important component of therapy. Some compounds require liver test (LT) monitoring, with the frequency detailed in the product label. Compliance with these instructions is generally unknown.The goal of this short study was to describe LT compliance for compounds with monitoring recommended at 2-week intervals or more frequently in three US administrative claims databases.The sample was drawn from three US claims databases during the period 1 January 2015 through 30 June 2018. This study examined nine compounds and five types of LTs. We looked at compounds in a published list of drugs requiring LTs at 2-week intervals or more frequently. Descriptive statistics about the days between tests were reported, as were the number and proportion of tests associated with each drug that met the recommended frequency.Compliance was 33% with four drugs (ketoconazole, succimer, pentamidine, and felbamate) and 60% with five drugs (oxaliplatin, rifampin, tolcapone, albendazole, and azathioprine). Among drugs with more than 1000 drug eras observed (all but succimer and tolcapone), LT compliance was highest for oxaliplatin (75.3%) and lowest for pentamidine (20.6%), with little difference in overall compliance by type of test (range 41-46).Compliance with frequent LT monitoring differed for the drugs examined. Two strata were found: compliance 60% (oxaliplatin, rifampin, tolcapone, albendazole, and azathioprine) and compliance 20-30% (ketoconazole, succimer, pentamidine, and felbamate). No drug reached 80% compliance.

Dopamine (DA) has been implicated in modulating multiple cognitive control processes, including the robust maintenance of task sets and memoranda in the face of distractors (cognitive stability) and, conversely, the ability to switch task sets or update the contents of working memory when it is advantageous to do so (cognitive flexibility). In humans, the limited specificity of available pharmacological probes has posed a challenge for understanding the mechanisms by which DA, acting on multiple receptor families across the PFC and striatum, differentially influences these cognitive processes. Using a within-subject, placebo-controlled design, we contrasted the impact of two mechanistically distinct DA drugs, tolcapone (an inhibitor of catechol-O-methyltransferase [COMT], a catecholamine inactivator) and bromocriptine (a DA agonist with preferential affinity for the D2 receptor), on the maintenance and switching of task rules. Given previous work demonstrating that drug effects on behavior are dependent on baseline DA tone, participants were stratified according to genetic polymorphisms associated with cortical (COMT Val158Met) and striatal (Taq1A) DA system function. Our results were partially consistent with an inverted-U-shaped relationship between tolcapone and robust rule maintenance (interaction with COMT genotype) and between bromocriptine and cued rule switching (interaction with Taq1A genotype). However, when task instructions were ambiguous, a third relationship emerged to explain drug effects on spontaneous task switching (interaction of COMT genotype and bromocriptine). Together, this pattern of results suggests that the effects of DA drugs vary not only as a function of the DA system component upon which they act but also on subtle differences in task demands and context.

Hydrophilic matrix tablets are a type of sustained release dosage form characterized by distributing a drug in a matrix that is usually polymeric. Tolcapone is a drug that inhibits the enzyme catechol-O-methyl transferase. In recent years, it has been shown that tolcapone is a potent inhibitor of the amyloid aggregation process of the transthyretin protein, and acts by stabilizing the structure of the protein, reducing the progression of familial amyloid polyneuropathy. The main objective of this study was to obtain a sustained release tablet of tolcapone for oral administration with a preferred dosage regimen of 1 administration every 12 or 24 h and manufactured, preferably, by direct compression. The SeDeM Diagram method has been used for the formulation development of hydrophilic matrix tablets. Given the characteristics of tolcapone, the excipient selected for the formation of the polymeric matrix was a high viscosity hydroxypropylmethylcellulose (Methocel&reg, K100M CR). A decrease in the particle size of tolcapone resulted in a slower dissolution release of the formulation when the concentration of the polymer Methocel&reg, K100M CR was below 29%. These surprising and novel results have given rise to patent number WO/2018/019997.

Catechol-O-methyl transferase inhibitors are currently used as first-line add-on therapy to levodopa for the treatment of end-of-dose motor fluctuations in Parkinson's disease patients, as they increase levodopa bioavailability. Several factors hamper the use of current available catechol-O-methyl transferase inhibitors, that is, the moderate efficacy and multiple dosing for entacapone and the risk of liver toxicity with tolcapone. Opicapone, a new long-acting, peripherally selective, once-daily catechol-O-methyl transferase inhibitor, was recently licensed in Europe. Two phase 3 double-blind clinical trials demonstrated opicapone efficacy in reducing OFF time by an average of about 60 minutes daily compared with placebo, without increasing ON time with troublesome dyskinesias. These effects were also maintained during a subsequent open-label extension consisting of 1-year follow-up. Opicapone showed a good safety profile. From June 2016, Opicapone received the approval for marketing authorization from the European Commission as adjunctive therapy to levodopa/DOPA decarboxylase inhibitors in patients with PD and end-of-dose motor fluctuations. We aimed to review the clinical pharmacological data of opicapone, summarize its clinical efficacy and safety issues, and discuss its potential role in the management of Parkinson's disease. © 2018 International Parkinson and Movement Disorder Society.

Rationale Impairment in time perception, a critical component of decision-making, represents a risk factor for psychiatric conditions including substance abuse. A therapeutic that ameliorates this impairment could be advantageous in the treatment of impulsivity and decision-making disorders. Objectives Here we hypothesize that the catechol-O-methyltransferase (COMT) inhibitor tolcapone, which increases dopamine tone in frontal cortex (Ceravolo et al Synapse 43:201–207, 2002), improves time perception, with predictive behavioral, genetic, and neurobiological components. Methods Subjects (n = 66) completed a duration estimation task and other behavioral testing in each of two sessions after receiving a single oral dose of tolcapone (200 mg) or placebo in randomized, double-blind, counterbalanced, crossover fashion. Resting state fMRI data were obtained in a subset of subjects (n = 40). Subjects were also genotyped for the COMT (rs4680) polymorphism. Results Time perception was significantly improved across four proximal time points ranging from 5 to 60 s (T(524) = 2.04, p = 0.042). The degree of this improvement positively correlated with subjective measures of stress, depression, and alcohol consumption and was most robust in carriers of the COMT Val158 allele. Using seed regions defined by a previous meta-analysis (Wiener et al Neuroimage 49:1728–1740, 2010), we found not only that a connection from right inferior frontal gyrus (RIFG) to right putamen decreases in strength on tolcapone versus placebo (p

Background A qualified consensus suggests that a combination of levodopa with a peripherally acting dopa decarboxylase inhibitor continues to present the gold standard treatment of Parkinson's disease (PD). However, as the disease progresses the therapeutic window of levodopa becomes narrowed. Pharmacological strategies for motor fluctuations are focused on providing less pulsatile and more continuous dopaminergic stimulation. Peripheral catechol-O-methyltransferase (COMT) inhibition improves the bioavailability of levodopa and results in a prolonged response. Objective The primary aim of this study was to investigate the efficacy and safety of the two available COMT inhibitors; entacapone and tolcapone and the recently introduced opicapone. Methods Electronic databases were systematically searched for original studies published within the last 37 years. In addition, lists of identified studies, reviews and their references were examined. Results Twelve studies fulfilled the inclusion criteria. 3701 patients with PD were included in this systematic review. Conclusions Adjuvant treatment of PD patients experiencing motor fluctuations with entacapone resulted in improvement of motor function and was well tolerated. Therefore, entacapone presented an acceptable benefit to risk ratio. Tolcapone appeared to result in a greater therapeutic effect. However, this was not consistent across all motor variables and studies, and thus would not support its use, given the current onerous monitoring that is required. Opicapone was not associated with adverse reactions in a phase III trial but did not present a greater efficacy than entacapone, and thus further studies are required in order to illustrate its cost effectiveness.

Tolcapone and entacapone are catechol-O-methyltransferase inhibitors used in patients with Parkinson's disease. For tolcapone, patients with liver failure have been reported with microvesicular steatosis observed in the liver biopsy of 1 patient. We therefore investigated the impact of tolcapone and entacapone on fatty acid metabolism in HepaRG cells exposed for 24 h and on acutely exposed mouse liver mitochondria. In HepaRG cells, tolcapone induced lipid accumulation starting at 100 µM, whereas entacapone was ineffective up to 200 µM. In HepaRG cells, tolcapone-inhibited palmitate metabolism and activation starting at 100 µM, whereas entacapone did not affect palmitate metabolism. In isolated mouse liver mitochondria, tolcapone inhibited palmitate metabolism starting at 5 µM and entacapone at 50 µM. Inhibition of palmitate activation could be confirmed by the acylcarnitine pattern in the supernatant of HepaRG cell cultures. Tolcapone-reduced mRNA and protein expression of long-chain acyl-CoA synthetase 1 (ACSL1) and protein expression of ACSL5, whereas entacapone did not affect ACSL expression. Tolcapone increased mRNA expression of the fatty acid transporter CD36/FAT, impaired the secretion of ApoB100 by HepaRG cells and reduced the mRNA expression of ApoB100, but did not relevantly affect markers of fatty acid binding, lipid droplet formation and microsomal lipid transfer. In conclusion, tolcapone impaired hepatocellular fatty acid metabolism at lower concentrations than entacapone. Tolcapone increased mRNA expression of fatty acid transporters, inhibited activation of long-chain fatty acids and impaired very low-density lipoprotein secretion, causing hepatocellular triglyceride accumulation. The findings may be relevant in patients with a high tolcapone exposure and preexisting mitochondrial dysfunction.

Catechol-O-methyltransferase (COMT) is a druggable biological target and COMT modulators have been widely applied in the treatment of various central and peripheral nervous system disorders. The interspecies differences of COMT were carefully investigated using 3-BTD (a newly developed fluorescent probe of COMT) methylation as the probe reaction, and liver S9 from humans and seven experimental animals including monkeys, dogs, mice, rats, minipigs, guinea pigs and New Zealand rabbits as the enzyme source. Metabolite profiling demonstrated that all the tested liver S9 samples from the different animals could catalyse 3-BTD methylation but displayed significant differences in reaction rate. Also, the differential effects of tolcapone (a potent inhibitor against COMT) on 3-BTD methylation among various species were observed. The apparent kinetic parameters and the maximum intrinsic clearances (Clint) for 3-BTD methylation in liver S9 from the different animals were determined, and the order of the Clint values for the formation of 3-BTD was RLS9 > DLS9 ≈ PLS9 > MLS9 > CyLS9 > RaLS9 > GpLS9 > HLS9. These findings are helpful for further exploring COMT-associated biological processes in animal models, as well as for developing therapeutic molecules that target COMT.

After Alzheimer's disease, Parkinson's disease (PD) has taken second place in becoming one of the most commonly occurring neurological diseases being responsible for a number of disabling motor symptoms ranging from bradykinesia, akinesia, tremors to rigidity, that mostly targets the elderly population and severely disrupts their quality of life. The true underlying pathology of PD yet remains a mystery, however, recent advances in the field have pointed towards the production of α-synuclein aggregates, oxidative stress, and an imbalance between levels of acetylcholine and dopamine neurotransmitters in the brain that have been shown to result in loss of coordinated movement. Current treatments of PD include the gold standard dopamine precursor L-dopa, dopamine agonists pergolide and bromocriptine, catechol-o-methyl transferases inhibitors, entacapone and tolcapone and monoamine oxidase inhibitors such as Selegine and Rasagiline amongst several other drugs. While these drugs are successful in treating motor symptoms of the disease, they do so with a plethora of side effects that are especially debilitating to the elderly. In the recent years, a considerable amount of attention has been shifted towards phytocompounds such as flavonoids and green tea catechins due to promising experimental results. In this review, we have compiled phytocompounds that have shown potent activity against some of the most important targets for antiparkinsonian therapy. These compounds have exhibited activities that transcend the limits of simply attenuating mitochondrial oxidative stress and have opened doors to the discovery of novel lead compounds for newer, efficacious antiparkinsonian therapies with wider therapeutic windows.

The enzymes, catechol O-methyltransferase (COMT) and monoamine oxidase (MAO) are important drug targets, and inhibitors of these enzymes are established therapy for symptomatic Parkinson’s disease (PD). COMT inhibitors enhance the bioavailability of levodopa to the brain, and therefore are combined with levodopa for the treatment of motor fluctuations in PD. Inhibitors of the MAO-B isoform, in turn, are used as monotherapy or in conjunction with levodopa in PD, and function by reducing the central degradation of dopamine. It has been reported that 1-tetralone and 1-indanone derivatives are potent and specific inhibitors of MAO-B, while compounds containing the nitrocatechol moiety (e.g. tolcapone and entacapone) are often potent COMT inhibitors. The present study attempted to discover compounds that exhibit dual COMT and MAO-B inhibition by synthesizing series of 1-tetralone, 1-indanone and related derivatives substituted with the nitrocatechol moiety. These compounds are structurally related to series of nitrocatechol derivatives of chalcone that have recently been investigated as potential dual COMT/MAO inhibitors. The results show that 4-chromanone derivative (7) is the most promising dual inhibitor with IC50 values of 0.57 and 7.26 μM for COMT and MAO-B, respectively, followed by 1-tetralone derivative (4d) with IC50 values of 0.42 and 7.83 μM for COMT and MAO-B, respectively. Based on their potent inhibition of COMT, it may be concluded that nitrocatechol compounds investigated in this study are appropriate for peripheral COMT inhibition, which represents an important strategy in the treatment of PD.