The mitochondrial enzymes seem to be next target for molecular design in term of Alzheimer Disease (AD) treatment. They are well known for their interaction with ß-amyloid and they are subsequently responsible for disruption of cell homeostasis and cell death. The inhibition of ß-amyloid interaction with mitochondrial enzymes by small modulators might prevent neuronal cell loss and thus improve progress of AD. Up-to-date, only few mitochondrial enzyme modulators were published and their design, synthesis and evaluation will be highly progressive in near future. The main aim of the project is development of convenient candidates (small molecules) for further preclinical research.

Mitochondriální enzymy jsou jedním z možných cílů vývoje nových sloučenin pro léčbu Alzheimerovy nemoci. Tyto enzymy jsou dobře známy díky své interakci s ß-amyloidem, následnému porušení homeostázy buňky a buněčné smrti. Inhibice interakce těchto enzymů a ß-amyloidu pomocí molekul malých modulátorů by proto mohla zabránit ztrátě nervových buněk, a tak zpomalit progresi Alzheimerovy nemoci. Dosud bylo v literatuře publikováno pouze malé množství molekul s modulačním účinkem na mitochondriální enzymy, a proto se bude jejich design, příprava a testování rychle rozvíjet v blízké budoucnosti. Hlavní cílem projektu je vývoj vhodných kandidátů (malých modulátorů) pro budoucí preklinické testování.

• MeSH
• aktivace enzymů MeSH
• intravitální mikroskopie MeSH
• mitochondriální proteiny MeSH
• neurodegenerativní nemoci farmakoterapie   MeSH
• nootropní látky MeSH
• regulace genové exprese enzymů MeSH
• techniky in vitro MeSH

• Konspekt
• Patologie. Klinická medicína
• NLK Obory
• neurologie
• biochemie
• NLK Publikační typ
• závěrečné zprávy o řešení grantu AZV MZ ČR

Several neurodegenerative disorders including Alzheimer's disease (AD) have been connected with deregulation of casein kinase 1 (CK1) activity. Inhibition of CK1 therefore presents a potential therapeutic strategy against such pathologies. Recently, novel class of CK1-specific inhibitors with N-(benzo[d]thiazol-2-yl)-2-phenylacetamide structural scaffold has been discovered. 1-(benzo[d]thiazol-2-yl)-3-phenylureas, on the other hand, are known inhibitors amyloid-beta binding alcohol dehydrogenase (ABAD), an enzyme also involved in pathophysiology of AD. Based on their tight structural similarity, we decided to evaluate series of previously published benzothiazolylphenylureas, originally designed as ABAD inhibitors, for their inhibitory activity towards CK1. Several compounds were found to be submicromolar CK1 inhibitors. Moreover, two compounds were found to inhibit both, ABAD and CK1. Such dual-activity could be of advantage for AD treatment, as it would simultaneously target two distinct pathological processes involved in disease's progression. Based on PAMPA testing both compounds were suggested to permeate the blood-brain barrier, which makes them, together with their unique dual activity, interesting lead compounds for further development.

• MeSH
• 3-hydroxyacyl-CoA-dehydrogenasy metabolismus   MeSH
• fenylmočovinové sloučeniny chemie   farmakologie   MeSH
• inhibitory enzymů chemie   farmakologie   MeSH
• kasein kinasa I antagonisté a inhibitory   metabolismus   MeSH
• lidé MeSH
• molekulární struktura MeSH
• neurodegenerativní nemoci farmakoterapie   metabolismus   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Alzheimer's disease (AD) is a neurodegenerative disorder associated with an excessive accumulation of amyloid-beta peptide (Aβ). Based on the multifactorial nature of AD, preparation of multi-target-directed ligands presents a viable option to address more pathological events at one time. A novel class of asymmetrical disubstituted indolyl thioureas have been designed and synthesized to interact with monoamine oxidase (MAO) and/or amyloid-binding alcohol dehydrogenase (ABAD). The design combines the features of known MAO inhibitors scaffolds (e.g. rasagiline or ladostigil) and a frentizole moiety with potential to interact with ABAD. Evaluation against MAO identified several compounds that inhibited in the low to moderate micromolar range. The most promising compound (19) inhibited human MAO-A and MAO-B with IC50 values of 6.34μM and 0.30μM, respectively. ABAD activity evaluation did not show any highly potent compound, but the compound series allowed identification of structural features to assist the future development of ABAD inhibitors. Finally, several of the compounds were found to be potent inhibitors of horseradish peroxidase (HRP), preventing the use of the Amplex™ Red assay to detect hydrogen peroxide produced by MAO, highlighting the need for serious precautions when using an enzyme-coupled assay.

• MeSH
• 3-hydroxyacyl-CoA-dehydrogenasy antagonisté a inhibitory   metabolismus   MeSH
• Alzheimerova nemoc farmakoterapie   metabolismus   MeSH
• benzothiazoly chemie   farmakologie   MeSH
• fenylmočovinové sloučeniny chemie   farmakologie   MeSH
• inhibitory enzymů chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• molekulární struktura MeSH
• monoaminoxidasa metabolismus   MeSH
• thiomočovina chemická syntéza   chemie   farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Background: The mitochondrial enzyme amyloid beta-binding alcohol dehydrogenase (ABAD) also known as 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10) has been connected with the pathogenesis of Alzheimer's disease (AD). ABAD/ 17β-HSD10 is a binding site for the amyloid-beta peptide (Aβ) inside the mitochondrial matrix where it exacerbates Aβ toxicity. Interaction between these two proteins triggers a series of events leading to mitochondrial dysfunction as seen in AD. Methods: As ABAD's enzymatic activity is required for mediating Aβ toxicity, its inhibition presents a promising strategy for AD treatment. In this study, a series of new benzothiazolylurea analogues have been prepared and evaluated in vitro for their potency to inhibit ABAD/ 17β-HSD10 enzymatic activity. The most potent compounds have also been tested for their cytotoxic properties and their ability to permeate through blood-brain barrier has been predicted. To explain the structure-activity relationship QSAR and pharmacophore studies have been performed. Results and conclusions: Compound 12 was identified being the most promising hit compound with good inhibitory activity (IC50 = 3.06 ± 0.40μM) and acceptable cytotoxicity profile comparable to the parent compound of frentizole. The satisfactory physical-chemical properties suggesting its capability to permeate through BBB make compound 12 a novel lead structure for further development and biological assessment.

• MeSH
• Alzheimerova nemoc * farmakoterapie   MeSH
• benzothiazoly terapeutické užití   MeSH
• guanidin terapeutické užití   MeSH
• inhibitory enzymů chemická syntéza   terapeutické užití   MeSH
• lidé MeSH
• močovina terapeutické užití   MeSH
• neuroprotektivní látky * chemická syntéza   terapeutické užití   MeSH
• oxidoreduktasy antagonisté a inhibitory   škodlivé účinky   MeSH
• příprava léků metody   MeSH
• techniky in vitro metody   MeSH
• thiomočovina terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• klinická studie 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

3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) are widely used drugs for lowering blood lipid levels and preventing cardiovascular diseases. However, statins can have serious adverse effects, which may be related to development of mitochondrial dysfunctions. The aim of study was to demonstrate the in vivo effect of high and therapeutic doses of statins on mitochondrial respiration in blood platelets. Model approach was used in the study. Simvastatin was administered to rats at a high dose for 4 weeks. Humans were treated with therapeutic doses of rosuvastatin or atorvastatin for 6 weeks. Platelet mitochondrial respiration was measured using high-resolution respirometry. In rats, a significantly lower physiological respiratory rate was found in intact platelets of simvastatin-treated rats compared to controls. In humans, no significant changes in mitochondrial respiration were detected in intact platelets; however, decreased complex I-linked respiration was observed after statin treatment in permeabilized platelets. We propose that the small in vivo effect of statins on platelet energy metabolism can be attributed to drug effects on complex I of the electron transport system. Both intact and permeabilized platelets can be used as a readily available biological model to study changes in cellular energy metabolism in patients treated with statins.

• MeSH
• buněčné dýchání účinky léků   MeSH
• dyslipidemie farmakoterapie   MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• mitochondrie účinky léků   MeSH
• statiny škodlivé účinky   MeSH
• trombocyty účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Amyloid-beta peptide (Aβ) has been recognized to interact with numerous proteins, which may lead to pathological changes in cell metabolism of Alzheimer's disease (AD) patients. One such known metabolic enzyme is mitochondrial amyloid-binding alcohol dehydrogenase (ABAD), also known as 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10). Altered enzyme function caused by the Aβ-ABAD interaction, was previously shown to cause mitochondrial distress and a consequent cytotoxic effect, therefore providing a feasible target in AD drug development. Based on previous frentizole derivatives studies, we report two novel series of benzothiazolyl ureas along with novel insights into the structure and activity relationships for inhibition of ABAD. Two compounds (37, 39) were identified as potent ABAD inhibitors, where compound 39 exhibited comparable cytotoxicity with the frentizole standard; however, one-fold higher cytotoxicity than the parent riluzole standard. The calculated and experimental physical chemical properties of the most potent compounds showed promising features for blood-brain barrier penetration.

• MeSH
• 3-hydroxyacyl-CoA-dehydrogenasy antagonisté a inhibitory   metabolismus   MeSH
• Alzheimerova nemoc farmakoterapie   MeSH
• benzothiazoly chemie   farmakologie   MeSH
• CHO buňky MeSH
• Cricetulus MeSH
• inhibitory enzymů chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• močovina analogy a deriváty   chemie   farmakologie   MeSH
• molekulární struktura MeSH
• racionální návrh léčiv * MeSH
• viabilita buněk účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Current possibilities of Alzheimer's disease (AD) treatment are very limited and are based on administration of cholinesterase inhibitors (donepezil, rivastigmine, galantamine) and/or N-methyl-d-aspartate receptor antagonist, memantine. Newly synthesized drugs affect multiple AD pathophysiological pathways and can act as inhibitors of cholinesterases (AChE, BuChE), inhibitors of monoamine oxidases (MAO-A, MAO-B), modulators of mitochondrial permeability transition pores, modulators of amyloid-beta binding alcohol dehydrogenase and antioxidants. Effects of clinically used as well as newly developed AD drugs were studied in relation to energy metabolism and mitochondrial functions, including oxidative phosphorylation, activities of enzymes of citric acid cycle or electron transfer system, mitochondrial membrane potential, calcium homeostasis, production of reactive oxygen species and MAO activity.

• MeSH
• Alzheimerova nemoc farmakoterapie   metabolismus   patologie   MeSH
• energetický metabolismus účinky léků   MeSH
• inhibitory MAO chemie   metabolismus   farmakologie   terapeutické užití   MeSH
• lidé MeSH
• mitochondrie účinky léků   metabolismus   MeSH
• objevování léků metody   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Some therapeutic and/or adverse effects of drugs may be related to their effects on mitochondrial function. The effects of simvastatin, resveratrol, coenzyme Q10, acetylcysteine, and acetylcarnitine on Complex I-, Complex II-, or Complex IV-linked respiratory rate were determined in isolated brain mitochondria. The protective effects of these biologically active compounds on the calcium-induced decrease of the respiratory rate were also studied. We observed a significant inhibitory effect of simvastatin on mitochondrial respiration (IC50 = 24.0 μM for Complex I-linked respiration, IC50 = 31.3 μM for Complex II-linked respiration, and IC50 = 42.9 μM for Complex IV-linked respiration); the inhibitory effect of resveratrol was found at very high concentrations (IC50 = 162 μM for Complex I-linked respiration, IC50 = 564 μM for Complex II-linked respiration, and IC50 = 1454 μM for Complex IV-linked respiration). Concentrations required for effective simvastatin- or resveratrol-induced inhibition of mitochondrial respiration were found much higher than concentrations achieved under standard dosing of these drugs. Acetylcysteine and acetylcarnitine did not affect the oxygen consumption rate of mitochondria. Coenzyme Q10 induced an increase of Complex I-linked respiration. The increase of free calcium ions induced partial inhibition of the Complex I+II-linked mitochondrial respiration, and all tested drugs counteracted this inhibition. None of the tested drugs showed mitochondrial toxicity (characterized by respiratory rate inhibition) at drug concentrations achieved at therapeutic drug intake. Resveratrol, simvastatin, and acetylcarnitine had the greatest neuroprotective potential (characterized by protective effects against calcium-induced reduction of the respiratory rate).

• MeSH
• acetylcystein farmakologie   MeSH
• acylkarnitin farmakologie   MeSH
• buněčné dýchání účinky léků   MeSH
• mitochondrie účinky léků   metabolismus   MeSH
• mozek účinky léků   MeSH
• neuroprotektivní látky farmakologie   MeSH
• prasata MeSH
• respirační komplex IV metabolismus   MeSH
• simvastatin farmakologie   MeSH
• spotřeba kyslíku účinky léků   MeSH
• stilbeny farmakologie   MeSH
• ubichinon analogy a deriváty   farmakologie   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Progress in understanding the role of monoamine neurotransmission in pathophysiology of neuropsychiatric disorders was made after the discovery of the mechanisms of action of psychoactive drugs, including monoamine oxidase (MAO) inhibitors. The increase in monoamine neurotransmitter availability, decrease in hydrogen peroxide production, and neuroprotective effects evoked by MAO inhibitors represent an important approach in the development of new drugs for the treatment of mental disorders and neurodegenerative diseases. New drugs are synthesized by acting as multitarget-directed ligands, with MAO, acetylcholinesterase, and iron chelation as targets. Basic information is summarized in this paper about the drug-induced regulation of monoaminergic systems in the brain, with a focus on MAO inhibition. Desirable effects of MAO inhibition include increased availability of monoamine neurotransmitters, decreased oxidative stress, decreased formation of neurotoxins, induction of pro-survival genes and antiapoptotic factors, and improved mitochondrial functions.

• MeSH
• duševní poruchy farmakoterapie   enzymologie   MeSH
• inhibitory MAO chemická syntéza   farmakologie   terapeutické užití   MeSH
• lidé MeSH
• monoaminoxidasa metabolismus   MeSH
• nervový přenos účinky léků   fyziologie   MeSH
• neurodegenerativní nemoci farmakoterapie   enzymologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH