Dementia is a syndrome caused by a brain disease in which higher cortical functions, including memory, thinking, orientation, learning, language, judgement, and others are impaired. The impairment of these functions causes significant limitations in the patient’s self-sufficiency over time. The number of cases is increasing exponentially due to the ageing population. This diagnosis significantly negatively affects the quality of life not only of patients, but also of their caregivers. Therefore, emphasis is now being placed on comrehensive therapy. This article serves as a brief overview of the pharmacological treatment. However, non-pharmacological approaches are also a very important part of therapy
Demence je syndrom způsobený onemocněním mozku, při kterém dochází k narušení vyšších kortikálních funkcí, k nimž patří paměť, myšlení, orientace, schopnost učení, jazyk, úsudek a další. Porucha těchto funkcí způsobuje časem významné omezení soběstačnosti pacienta. Počet případů vzhledem ke stárnoucí populaci exponenciálně narůstá a tato nemoc výrazně negativně ovlivňuje kvalitu života nejen pacientů, ale i jejich pečovatelů. Proto je v současné době kladen velký důraz na komplexní terapii této choroby. Článek slouží jako stručný přehled farmakologické léčby, nicméně velmi důležitou součástí terapie jsou i nefarmakologické přístupy.
- MeSH
- demence * diagnóza terapie MeSH
- lidé MeSH
- nootropní látky farmakologie terapeutické užití MeSH
- psychosociální intervence MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Concerned by the urgent need to explore new approaches for the treatment of Alzheimer's disease, we herein describe the synthesis and evaluation of new multitarget molecules. In particular, we have focused our attention on modulating the activity of cholinesterases (AChE, BuChE) in order to restore the levels of the neurotransmitter acetylcholine, and of O-GlcNAcase (OGA), which is associated with hyperphosphorylation of tau protein, in turn related to the formation of neurofibrillary tangles in the brain. Specifically, we considered the possibility of using carbohydrate-fused 1,3-selenazolines, decorated with a 2-alkylamino or 2-alkoxy moieties. On the one hand, the presence of a selenium atom might be useful in modulating the intrinsic oxidative stress in AD. On the other hand, such bicyclic structure might behave as a transition state analogue of OGA hydrolysis. Moreover, upon protonation, it could mimic the ammonium cation of acetylcholine. The lead compound, bearing a propylamino moiety on C-2 position of the selenazoline motif, proved to be a good candidate against AD; it turned out to be a strong inhibitor of BuChE (IC50 = 0.46 μM), the most prevalent cholinesterase in advanced disease stages, with a roughly 4.8 selectivity index in connection to AChE (IC50 = 2.2 μM). This compound exhibited a roughly 12-fold increase in activity compared to galantamine, one of the currently marketed drugs against AD, and a selective AChE inhibitor, and virtually the same activity as rivastigmine, a selective BuChE inhibitor. Furthermore, it was also endowed with a strong inhibitory activity against human OGA, within the nanomolar range (IC50 = 0.053 μM for hOGA, >100 μM for hHexB), and, thus, with an outstanding selectivity (IC50(hHexB)/IC50(hOGA) > 1887). The title compounds also exhibited an excellent selectivity against a panel of glycosidases and a negligible cytotoxicity against tumor and non-tumor cell lines. Docking simulations performed on the three target enzymes (AChE, BuChE, and OGA) revealed the key interactions to rationalize the biological data.
- MeSH
- acetylcholin MeSH
- acetylcholinesterasa metabolismus MeSH
- Alzheimerova nemoc * farmakoterapie metabolismus MeSH
- beta-N-acetylhexosaminidasy * antagonisté a inhibitory MeSH
- cholinesterasové inhibitory * chemie MeSH
- cholinesterasy * metabolismus MeSH
- lidé MeSH
- nootropní látky farmakologie MeSH
- sacharidy MeSH
- simulace molekulového dockingu MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- antidepresiva tricyklická farmakologie škodlivé účinky terapeutické užití MeSH
- antidepresiva farmakologie škodlivé účinky terapeutické užití MeSH
- antipsychotika farmakologie škodlivé účinky terapeutické užití MeSH
- anxiolytika farmakologie škodlivé účinky terapeutické užití MeSH
- benzodiazepiny farmakologie škodlivé účinky terapeutické užití MeSH
- duševní poruchy farmakoterapie MeSH
- hypnotika a sedativa farmakologie škodlivé účinky terapeutické užití MeSH
- inhibitory MAO farmakologie škodlivé účinky terapeutické užití MeSH
- inhibitory zpětného vychytávání serotoninu a noradrenalinu farmakologie škodlivé účinky terapeutické užití MeSH
- lidé MeSH
- nootropní látky farmakologie škodlivé účinky terapeutické užití MeSH
- odvykací prostředky alkoholu farmakologie škodlivé účinky terapeutické užití MeSH
- psychotropní léky * farmakologie škodlivé účinky terapeutické užití MeSH
- selektivní inhibitory zpětného vychytávání serotoninu farmakologie škodlivé účinky terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
- MeSH
- antidepresiva farmakologie MeSH
- anxiolytika farmakologie MeSH
- Carthamus tinctorius * chemie metabolismus růst a vývoj MeSH
- chalkon analogy a deriváty MeSH
- fytoterapie MeSH
- lidé MeSH
- neuroprotektivní látky farmakologie MeSH
- nootropní látky farmakologie MeSH
- rostlinné extrakty * farmakologie terapeutické užití MeSH
- šalvěj červenokořenná MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
Plants of the Amaryllidaceae family are promising therapeutic tools for human diseases and have been used as alternative medicines. The specific secondary metabolites of this plant family, called Amaryllidaceae alkaloids (AA), have attracted considerable attention due to their interesting pharmacological activities. One of them, galantamine, is already used in the therapy of Alzheimer's disease as a long acting, selective, reversible inhibitor of acetylcholinesterase. One group of AA is the montanine-type, such as montanine, pancracine and others, which share a 5,11-methanomorphanthridine core. So far, only 14 montanine-type alkaloids have been isolated. Compared with other structural-types of AA, montanine-type alkaloids are predominantly present in plants in low concentrations, but some of them display promising biological properties, especially in vitro cytotoxic activity against different cancerous cell lines. The present review aims to summarize comprehensively the research that has been published on the Amaryllidaceae alkaloids of montanine-type.
- MeSH
- alkaloidy amarylkovitých chemie izolace a purifikace farmakologie MeSH
- Amaryllidaceae chemie metabolismus MeSH
- antiprotozoální látky chemie izolace a purifikace farmakologie MeSH
- antitumorózní látky fytogenní chemie izolace a purifikace farmakologie MeSH
- cholinesterasové inhibitory chemie izolace a purifikace farmakologie MeSH
- fenantridiny chemie izolace a purifikace farmakologie MeSH
- galantamin chemie izolace a purifikace farmakologie MeSH
- heterocyklické sloučeniny tetra- a více cyklické chemie izolace a purifikace farmakologie MeSH
- inhibiční koncentrace 50 MeSH
- isochinoliny chemie izolace a purifikace farmakologie MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nootropní látky chemie izolace a purifikace farmakologie MeSH
- rostlinné extrakty chemie MeSH
- sekundární metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Alzheimer's disease (AD) is one of the most significant neurodegenerative disorders and its symptoms mostly appear in aged people. Catechol-o-methyltransferase (COMT) is one of the known target enzymes responsible for AD. With the use of 23 known inhibitors of COMT, a query has been generated and validated by screening against the database of 1500 decoys to obtain the GH score and enrichment value. The crucial features of the known inhibitors were evaluated by the online ZINC Pharmer to identify new leads from a ZINC database. Five hundred hits were retrieved from ZINC Pharmer and by ADMET (absorption, distribution, metabolism, excretion, and toxicity) filtering by using FAF-Drug-3 and 36 molecules were considered for molecular docking. From the COMT inhibitors, opicapone, fenoldopam, and quercetin were selected, while ZINC63625100_413 ZINC39411941_412, ZINC63234426_254, ZINC63637968_451, and ZINC64019452_303 were chosen for the molecular dynamics simulation analysis having high binding affinity and structural recognition. This study identified the potential COMT inhibitors through pharmacophore-based inhibitor screening leading to a more complete understanding of molecular-level interactions.
- MeSH
- Alzheimerova nemoc farmakoterapie enzymologie patofyziologie MeSH
- exprese genu MeSH
- farmaceutické databáze MeSH
- inhibitory katechol-O-methyltransferasy chemie farmakologie MeSH
- interakční proteinové domény a motivy MeSH
- katechol-O-methyltransferasa chemie MeSH
- kinetika MeSH
- konformace proteinů, alfa-helix MeSH
- konformace proteinů, beta-řetězec MeSH
- lidé MeSH
- ligandy MeSH
- nootropní látky chemie farmakologie MeSH
- rychlé screeningové testy * MeSH
- simulace molekulární dynamiky MeSH
- simulace molekulového dockingu MeSH
- substrátová specifita MeSH
- terciární struktura proteinů MeSH
- termodynamika MeSH
- vazba proteinů MeSH
- vazebná místa MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Two new compounds (E)-2-(5,7-dibromo-3,3-dimethyl-3,4-dihydroacridin-1(2H)-ylidene)hydrazinecarbothiomide (3) and (E)-2-(5,7-dibromo-3,3-dimethyl-3,4-dhihydroacridin-1(2H)-ylidene)hydrazinecarboxamide (4) were synthesized and evaluated for their anticholinesterase activities. In vitro tests performed by NMR and Ellman's tests, pointed to a mixed kinetic mechanism for the inhibition of acetylcholinesterase (AChE). This result was corroborated through further docking and molecular dynamics studies, suggesting that the new compounds can work as gorge-spanning ligands by interacting with two different binding sites inside AChE. Also, in silico toxicity evaluation suggested that these new compounds can be less toxic than tacrine.
- MeSH
- acetylcholinesterasa chemie MeSH
- Alzheimerova nemoc farmakoterapie enzymologie patofyziologie MeSH
- enzymatické testy MeSH
- exprese genu MeSH
- interakční proteinové domény a motivy MeSH
- katalytická doména MeSH
- kinetika MeSH
- lidé MeSH
- ligandy MeSH
- nootropní látky chemická syntéza farmakologie MeSH
- racionální návrh léčiv MeSH
- sekundární struktura proteinů MeSH
- semikarbazony chemická syntéza farmakologie MeSH
- simulace molekulární dynamiky * MeSH
- simulace molekulového dockingu MeSH
- takrin farmakologie MeSH
- termodynamika MeSH
- vazba proteinů MeSH
- vodíková vazba MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: 6-chlorotacrine is a cholinesterase inhibitor showing good inhibitory potential, even better than parent compound tacrine, in vitro. Despite tacrine scaffold is broadly used for design and synthesis of novel compounds with anti-Alzheimer's potential, no in vivo effects have been investigated so far. Thus, basic toxicological and behavioural evaluation has been carried out throughout this study. METHODS: Maximum tolerated dose (MTD) and median lethal dose (LD50) were assessed in BALB/c mice and Wistar rats. Behavioural effects were observed in rats performing the multiple T-maze test, the water maze test and the step-through passive avoidance test. All outcomes were compared with the effects of parent compound - tacrine. RESULTS: The toxicity of 6-chlorotacrine was increased compared to tacrine with MTD 6.0/5.0 mg.kg-1 (i.m., male/female mice), 6.0/5.0 mg.kg-1 (i.p., male/female rats) and LD50 9.0 mg.kg-1 (male rats). At MTD doses, no histopathological changes and blood biochemistry abnormalities were observed except decreased plasma creatinine levels. 6-chlorotacrine showed good effects in the reversal of quinuclidinyl benzilate-induced amnesia. Best results were achieved at the dose of 1.8 mg.kg-1 (20% LD50) in the water maze test; the pro-cognitive effect was stronger than that of tacrine (5.2 mg.kg-1, 20% LD50). Other doses tested (0.9 mg.kg-1 and 2.7 mg.kg-1) showed similar effects as tacrine in the water maze, multiple T-maze and passive avoidance test. CONCLUSION: Observed effects predetermined 6-chlorotacrine as a potent parent compound for the synthesis of novel multifactorial drugs intended to the treatment of Alzheimer's disease. Even though 6- chlorotacrine showed in vivo beneficial effect with no signs of toxicity, further tests on the field of biochemistry and pharmacology are essential to disclose the exact mechanism of action, safety evaluation and the metabolic fate of the compound after the repeated administration.
- MeSH
- bludiště - učení účinky léků MeSH
- cholinesterasové inhibitory chemie farmakologie toxicita MeSH
- myši inbrední BALB C MeSH
- nootropní látky chemie farmakologie toxicita MeSH
- potkani Wistar MeSH
- preklinické hodnocení léčiv MeSH
- takrin analogy a deriváty chemie farmakologie toxicita MeSH
- učení vyhýbat se účinky léků MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Impairment of mitochondrial metabolism, particularly the electron transport chain (ETC), as well as increased oxidative stress might play a significant role in pathogenesis of Alzheimer's disease (AD). Some effects of drugs used for symptomatic AD treatment may be related to their direct action on mitochondrial function. In vitro effects of pharmacologically different cognitives (galantamine, donepezil, rivastigmine, 7-MEOTA, memantine) and nootropic drugs (latrepirdine, piracetam) were investigated on selected mitochondrial parameters: activities of ETC complexes I, II + III, and IV, citrate synthase, monoamine oxidase (MAO), oxygen consumption rate, and hydrogen peroxide production of pig brain mitochondria. Complex I activity was decreased by galantamine, donepezil, and memantine; complex II + III activity was increased by galantamine. None of the tested drugs caused significant changes in the rate of mitochondrial oxygen consumption, even at high concentrations. Except galantamine, all tested drugs were selective MAO-A inhibitors. Latrepirdine, donepezil, and 7-MEOTA were found to be the most potent MAO-A inhibitors. Succinate-induced mitochondrial hydrogen peroxide production was not significantly affected by the drugs tested. The direct effect of cognitives and nootropics used in the treatment of AD on mitochondrial respiration is relatively small. The safest drugs in terms of disturbing mitochondrial function appear to be piracetam and rivastigmine. The MAO-A inhibition by cognitives and nootropics may also participate in mitochondrial neuroprotection. The results support the future research aimed at measuring the effects of currently used drugs or newly synthesized drugs on mitochondrial functioning in order to understand their mechanism of action.
- MeSH
- Alzheimerova nemoc metabolismus MeSH
- cholinesterasové inhibitory farmakologie MeSH
- galantamin metabolismus MeSH
- indany farmakologie MeSH
- kognice účinky léků MeSH
- memantin farmakologie MeSH
- mitochondrie účinky léků metabolismus MeSH
- monoaminoxidasa účinky léků metabolismus MeSH
- mozek účinky léků metabolismus MeSH
- nootropní látky farmakologie MeSH
- piperidiny farmakologie MeSH
- prasata MeSH
- rivastigmin farmakologie MeSH
- spotřeba kyslíku účinky léků MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
