RNA splicing, the process of intron removal from pre-mRNA, is essential for the regulation of gene expression. It is controlled by the spliceosome, a megadalton RNA-protein complex that assembles de novo on each pre-mRNA intron through an ordered assembly of intermediate complexes1,2. Spliceosome activation is a major control step that requires substantial protein and RNA rearrangements leading to a catalytically active complex1-5. Splicing factor 3B subunit 1 (SF3B1) protein-a subunit of the U2 small nuclear ribonucleoprotein6-is phosphorylated during spliceosome activation7-10, but the kinase that is responsible has not been identified. Here we show that cyclin-dependent kinase 11 (CDK11) associates with SF3B1 and phosphorylates threonine residues at its N terminus during spliceosome activation. The phosphorylation is important for the association between SF3B1 and U5 and U6 snRNAs in the activated spliceosome, termed the Bact complex, and the phosphorylation can be blocked by OTS964, a potent and selective inhibitor of CDK11. Inhibition of CDK11 prevents spliceosomal transition from the precatalytic complex B to the activated complex Bact and leads to widespread intron retention and accumulation of non-functional spliceosomes on pre-mRNAs and chromatin. We demonstrate a central role of CDK11 in spliceosome assembly and splicing regulation and characterize OTS964 as a highly selective CDK11 inhibitor that suppresses spliceosome activation and splicing.
- MeSH
- aktivace enzymů účinky léků MeSH
- chinolony farmakologie MeSH
- chromatin metabolismus MeSH
- cyklin-dependentní kinasy * antagonisté a inhibitory metabolismus MeSH
- fosfoproteiny * chemie metabolismus MeSH
- fosforylace MeSH
- malý jaderný ribonukleoprotein U2 * chemie metabolismus MeSH
- prekurzory RNA * genetika metabolismus MeSH
- sestřih RNA * účinky léků MeSH
- spliceozomy * účinky léků metabolismus MeSH
- threonin metabolismus MeSH
- Publikační typ
- časopisecké články MeSH
In this pilot study, a series of new 3,4-dihydroquinolin-2(1H)-one derivatives as potential dopamine receptor D2 (D2R) modulators were synthesized and evaluated in vitro. The preliminary structure-activity relationship disclosed that compound 5e exhibited the highest D2R affinity among the newly synthesized compounds. In addition, 5e showed a very low cytotoxic profile and a high probability to cross the blood-brain barrier, which is important considering the observed affinity. However, molecular modelling simulation revealed completely different binding mode of 5e compared to USC-D301, which might be the culprit of the reduced affinity of 5e toward D2R in comparison with USC-D301.
- MeSH
- aripiprazol chemická syntéza farmakologie MeSH
- buněčná smrt MeSH
- centrální nervový systém účinky léků MeSH
- chinolony chemická syntéza chemie farmakologie MeSH
- CHO buňky MeSH
- Cricetulus MeSH
- hematoencefalická bariéra účinky léků patologie MeSH
- ligandy MeSH
- molekulární modely MeSH
- racionální návrh léčiv MeSH
- receptory dopaminu D2 chemie metabolismus MeSH
- vazebná místa MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The identification and quantification of mitochondrial effects of novel antipsychotics (brexpiprazole, cariprazine, loxapine, and lurasidone) were studied in vitro in pig brain mitochondria. Selected parameters of mitochondrial metabolism, electron transport chain (ETC) complexes, citrate synthase (CS), malate dehydrogenase (MDH), monoamine oxidase (MAO), mitochondrial respiration, and total ATP and reactive oxygen species (ROS) production were evaluated and associated with possible adverse effects of drugs. All tested antipsychotics decreased the ETC activities (except for complex IV, which increased in activity after brexpiprazole and loxapine addition). Both complex I- and complex II-linked respiration were dose-dependently inhibited, and significant correlations were found between complex I-linked respiration and both complex I activity (positive correlation) and complex IV activity (negative correlation). All drugs significantly decreased mitochondrial ATP production at higher concentrations. Hydrogen peroxide production was significantly increased at 10 μM brexpiprazole and lurasidone and at 100 μM cariprazine and loxapine. All antipsychotics acted as partial inhibitors of MAO-A, brexpiprazole and loxapine partially inhibited MAO-B. Based on our results, novel antipsychotics probably lacked oxygen uncoupling properties. The mitochondrial effects of novel antipsychotics might contribute on their adverse effects, which are mostly related to decreased ATP production and increased ROS production, while MAO-A inhibition might contribute to their antidepressant effect, and brexpiprazole- and loxapine-induced MAO-B inhibition might likely promote neuroplasticity and neuroprotection. The assessment of drug-induced mitochondrial dysfunctions is important in development of new drugs as well as in the understanding of molecular mechanism of adverse or side drug effects.
- MeSH
- adenosintrifosfát biosyntéza MeSH
- antipsychotika klasifikace farmakologie MeSH
- chinolony farmakologie MeSH
- elektronový transportní řetězec účinky léků MeSH
- energetický metabolismus účinky léků MeSH
- inhibitory MAO farmakologie MeSH
- loxapin farmakologie MeSH
- lurasidon hydrochlorid farmakologie MeSH
- mitochondrie účinky léků metabolismus MeSH
- peroxid vodíku metabolismus MeSH
- piperaziny farmakologie MeSH
- prasata MeSH
- reaktivní formy kyslíku metabolismus MeSH
- receptory neurotransmiterů účinky léků MeSH
- spotřeba kyslíku účinky léků MeSH
- thiofeny farmakologie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Noví parciální agonisté dopaminu slibují v terapii schizofrenie vyváženost mezi dobrou účinností a příznivým spektrem nežádoucích účinků. Jsou vhodnými léky k řešení metabolického syndromu způsobeného jinými druhy antipsychotik. Převedli jsme úspěšně pacienta z terapie 210 mg depotního olanzapinu na 4 mg brexpiprazolu. Brexpiprazol vykazuje velmi nízké hodnoty přerušení léčby z důvodu nežádoucích účinků, a je proto možnou alternativou v takových případech, kdy si nemůžeme vybrat mezi ostatními antipsychotiky, která máme k dispozici v injekcích.
New partial dopamine agonists promise a balance between good efficacy and a favorable spectrum of side effects in the treatment of schizophrenia. They are suitable drugs to solve the metabolic syndrome caused by other types of antipsychotics. We successfully transferred a patient from 210 mg depot olanzapine to 4 mg brexpiprazole. Brexpiprazole has very low discontinuation rates due to side effects and is therefore a possible alternative in cases where we cannot choose from other antipsychotics available for injection.
- Klíčová slova
- brexpiprazol,
- MeSH
- agonisté dopaminu terapeutické užití MeSH
- chinolony farmakologie terapeutické užití MeSH
- dospělí MeSH
- lidé MeSH
- metabolické vedlejší účinky léčivých látek MeSH
- metabolický syndrom chemicky indukované MeSH
- olanzapin škodlivé účinky terapeutické užití MeSH
- paranoidní schizofrenie * farmakoterapie MeSH
- serotoninové látky terapeutické užití MeSH
- thiofeny farmakologie terapeutické užití MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
V současné době je pro udržovací léčbu astmatu k dispozici celá řada inhalačních léků a jejich kombinací v různých inhalačních systémech. V květnu 2020 byl Evropskou lékovou agenturou (EMA) schválen pro léčbu astmatu léčivý přípravek Atectura® Breezhaler®, který obsahuje fixní dvojkombinaci indakaterol/mometason furoát a je podáván jednou denně prostřednictvím práškového inhalátoru.
Currently, a variety of inhaled drugs and its combinations in different types of inhaler devices exist on the market that are available for the maintenance treatment of asthma. In May 2020, the European Medicines Agency (EMA) approved Atectura® Breezhaler® containing fixed combination of indacaterol and mometasone furoate administered once daily via a dry powder inhaler for the treatment of asthma.
- Klíčová slova
- Acectura breezhaler, Energzair breezhaler,
- MeSH
- agonisté beta-2-adrenergních receptorů aplikace a dávkování farmakologie MeSH
- antiastmatika MeSH
- aplikace inhalační MeSH
- betamethason aplikace a dávkování farmakologie MeSH
- bronchiální astma * farmakoterapie MeSH
- bronchodilatancia aplikace a dávkování MeSH
- chinolony aplikace a dávkování farmakologie MeSH
- fixní kombinace léků MeSH
- glykopyrrolát aplikace a dávkování farmakologie MeSH
- léková kontraindikace MeSH
- lékové interakce MeSH
- lidé MeSH
- nežádoucí účinky léčiv MeSH
- udržovací chemoterapie MeSH
- Check Tag
- lidé MeSH
- MeSH
- antagonisté muskarinových receptorů aplikace a dávkování farmakologie MeSH
- antiastmatika terapeutické užití MeSH
- aplikace inhalační MeSH
- bronchiální astma * farmakoterapie MeSH
- chinolony aplikace a dávkování farmakologie MeSH
- dvojitá slepá metoda MeSH
- glykopyrrolát aplikace a dávkování farmakologie MeSH
- indany aplikace a dávkování farmakologie MeSH
- kombinovaná farmakoterapie MeSH
- lidé MeSH
- mometason furoát aplikace a dávkování farmakologie MeSH
- udržovací chemoterapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- klinické zkoušky, fáze II MeSH
- klinické zkoušky, fáze III MeSH
- randomizované kontrolované studie MeSH
- Klíčová slova
- brexpiprazol,
- MeSH
- agonisté dopaminu * farmakokinetika farmakologie terapeutické užití MeSH
- Alzheimerova nemoc farmakoterapie MeSH
- antipsychotika * farmakokinetika farmakologie terapeutické užití MeSH
- aripiprazol MeSH
- chinolony farmakologie terapeutické užití MeSH
- deprese farmakoterapie MeSH
- klinické zkoušky jako téma MeSH
- lidé MeSH
- receptory dopaminu D2 agonisté MeSH
- schizofrenie farmakoterapie MeSH
- serotoninové receptory 5-HT2 - agonisté MeSH
- thiofeny farmakologie terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
In this communication, we report the synthesis and cholinesterase (ChE)/monoamine oxidase (MAO) inhibition of 19 quinolinones (QN1-19) and 13 dihydroquinolinones (DQN1-13) designed as potential multitarget small molecules (MSM) for Alzheimer's disease therapy. Contrary to our expectations, none of them showed significant human recombinant MAO inhibition, but compounds QN8, QN9, and DQN7 displayed promising human recombinant acetylcholinesterase (hrAChE) and butyrylcholinesterase (hrBuChE) inhibition. In particular, molecule QN8 was found to be a potent and quite selective non-competitive inhibitor of hrAChE (IC50 = 0.29 μM), with Ki value in nanomolar range (79 nM). Pertinent docking analysis confirmed this result, suggesting that this ligand is an interesting hit for further investigation.
- MeSH
- acetylcholinesterasa metabolismus MeSH
- Alzheimerova nemoc farmakoterapie MeSH
- chinolony farmakologie MeSH
- cholinesterasové inhibitory farmakologie MeSH
- inhibiční koncentrace 50 MeSH
- inhibitory MAO farmakologie MeSH
- kinetika MeSH
- lidé MeSH
- ligandy MeSH
- magnetická rezonanční spektroskopie MeSH
- monoaminoxidasa metabolismus MeSH
- preklinické hodnocení léčiv MeSH
- racionální návrh léčiv MeSH
- rekombinantní proteiny metabolismus MeSH
- simulace molekulového dockingu MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
We have synthesized a series of 2-phenyl-3-hydroxy-4(1H)-quinolinone derivatives substituted with one or more fluorine atoms on the quinolone backbone as well as on phenyl ring. The derivatives bearing more fluorine atoms were subjected to modification by nucleophilic substitutions by thiophenol, morpholine, and piperazine derivative. We have tested the prepared compounds in cytotoxic activity assay against cancer cell lines. Four derivatives exhibited micromolar values of IC50 against some of the cancer cell lines, and we have subjected them to cell cycle analysis on CCRF-CEM. Moreover, most active 7-fluoro-3-hydroxy-2-phenyl-6-(phenylthio)quinolin-4(1H)-one inhibits mitosis progression. Cell cycle analysis, in vitro tubulin polymerization assay, and tubulin imaging in cells indicated that the anticancer activity of thiophenol derivative is associated with its ability to inhibit microtubule formation.
- MeSH
- chinolony chemická syntéza chemie farmakologie MeSH
- halogenace MeSH
- HCT116 buňky MeSH
- lidé MeSH
- modulátory tubulinu chemická syntéza chemie farmakologie MeSH
- molekulární struktura MeSH
- polymerizace účinky léků MeSH
- tubulin metabolismus MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
distribution of auxin within plant tissues is of great importance for developmental plasticity, including root gravitropic growth. Auxin flow is directed by the subcellular polar distribution and dynamic relocalisation of auxin transporters such as the PIN-FORMED (PIN) efflux carriers, which can be influenced by the main natural plant auxin indole-3-acetic acid (IAA). Anthranilic acid (AA) is an important early precursor of IAA and previously published studies with AA analogues have suggested that AA may also regulate PIN localisation. Using Arabidopsis thaliana as a model species, we studied an AA-deficient mutant displaying agravitropic root growth, treated seedlings with AA and AA analogues and transformed lines to over-produce AA while inhibiting its conversion to downstream IAA precursors. We showed that AA rescues root gravitropic growth in the AA-deficient mutant at concentrations that do not rescue IAA levels. Overproduction of AA affects root gravitropism without affecting IAA levels. Treatments with, or deficiency in, AA result in defects in PIN polarity and gravistimulus-induced PIN relocalisation in root cells. Our results revealed a previously unknown role for AA in the regulation of PIN subcellular localisation and dynamics involved in root gravitropism, which is independent of its better known role in IAA biosynthesis.
- MeSH
- Arabidopsis účinky léků metabolismus MeSH
- chinolony farmakologie MeSH
- gravitropismus fyziologie MeSH
- kořeny rostlin anatomie a histologie účinky léků růst a vývoj fyziologie MeSH
- kyseliny indoloctové chemie metabolismus MeSH
- mutace genetika MeSH
- ortoaminobenzoáty chemie metabolismus farmakologie MeSH
- polarita buněk * účinky léků MeSH
- proteiny huseníčku metabolismus MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH