V rámci řešení tohoto projektu chceme zužitkovat získaná předběžná data při přípravě učinných konjugátů obsahující derivát melatoninu a inhibitor AChE - huprin. Tyto sloučeniny by měly disponovat multipotentním profilem v léčbě Alzheimerovy choroby zejména, ale nikoliv výlučně tím, že kombinují příznivý vliv cholinergní stimulace a antioxidační aktivitu. Vývoj léčiva zahrnuje proces od návrhu a organické syntézy i přes in vitro hodnocení účinnosti a bezpečnosti léčiva po in vivo validaci zahrnující studium kinetiky, toxicity a farmakodynamiky tak, aby bylo možné vybrat nejlepšího potenciálního kandidáta na léčivo . V rámci tohoto projektu základní výzkum (9%) je reprezentován syntézou nových sloučenin a zhodnocením vztahu mezi strukturou a biologickou aktivitou (SAR). Většinový aplikovaný výzkum (91%) zde představuje selekční mechanismus pro výběr nejlepšího kadnidáta, jeho in vivo ověření učinnosti a bezpečnosti s následnou aplikací patentové ochrany včetně potenciálního komerčního využití; We would like to exploit the obtained preliminary data in preparation of more active hybrids combining derivative of melatonin and AChE inhibitor – huprine. Such compounds should exert multipotent profile in Alzheimer ́s disease treatment by combining beneficial effect of mainly, but not exclusively, cholinergic enhancement and antioxidant activity. Funnel-like drug development process from design and synthesis though in vitro efficacy and safety evaluation to in vivo validation involving kinetic, toxic, pharmacodynamic and behavioral examination will be applied in order to select the best drug candidate. In this project, basic research (9%) represent the synthesis of novel compounds and the structure-biological activity relationship (SAR) evaluation. Applied research (91%) represents majority of the project, thus, the funnel-like selection of a drug candidate, its in vivo validation and subsequent patent protection application with commercial utilization.

• MeSH
• acetylcholinesterasa MeSH
• Alzheimerova nemoc farmakoterapie   MeSH
• cholinesterasové inhibitory terapeutické užití   MeSH
• intravitální mikroskopie MeSH
• melatonin terapeutické užití   MeSH
• tryptofan terapeutické užití   MeSH
• vyvíjení léků MeSH

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

Alzheimer's disease is debilitating neurodegenerative disorder in the elderly. Current therapy relies on administration of acetylcholinesterase inhibitors (AChEIs) -donepezil, rivastigmine, galantamine, and N-methyl-d-aspartate receptor antagonist memantine. However, their therapeutic effect is only short-term and stabilizes cognitive functions for up to 2 years. Given this drawback together with other pathological hallmarks of the disease taken into consideration, novel approaches have recently emerged to better cope with AD onset or its progression. One such strategy implies broadening the biological profile of AChEIs into so-called multi-target directed ligands (MTDLs). In this review article, we made comprehensive literature survey emphasising on donepezil template which was structurally converted into plethora of MTLDs preserving anti-cholinesterase effect and, at the same time, escalating the anti-oxidant potential, which was reported as a crucial role in the pathogenesis of the Alzheimer's disease.

• MeSH
• acetylcholinesterasa metabolismus   MeSH
• Alzheimerova nemoc farmakoterapie   metabolismus   MeSH
• antioxidancia chemie   farmakologie   MeSH
• cholinesterasové inhibitory chemie   farmakologie   MeSH
• indany chemie   farmakologie   MeSH
• lidé MeSH
• molekulární struktura MeSH
• piperidiny chemie   farmakologie   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

BACKGROUND: The design of new heterodimeric dual binding site acetylcholinesterase inhibitors constitutes the main goal-directed to the development of new anticholinesterase agents with the expanded pharmacological profile. Multi-target compounds are usually designed by combining in a hybrid molecule with two or more pharmacophoric moieties that are known to enable interaction with the selected molecular targets. METHODS: All compounds were tested for their inhibitory activity on human AChE/BChE. The Ellman´s method was used to determine inhibition kinetics and IC50 values. In order to predict passive bloodbrain penetration of novel compounds, modification of the parallel artificial membrane permeation assay has been used. Docking studies were performed in order to predict the binding modes of new hybrids with hAChE/ hBChE respectively. RESULTS: In this study, we described the design, synthesis, and evaluation of series tacrine-coumarin and tacrine-quinoline compounds which were found to show potential inhibition of ChEs and penetration of the blood-brain barrier. CONCLUSION: Tacrine-quinoline hybrids 7a exhibited the highest activity towards hBChE (IC50 = 0.97 µmol) and 7d towards hAChE (IC50 = 0.32 µmol). Kinetic and molecular modelling studies revealed that 7d was a mixed-type AChE inhibitor (Ki = 1.69 µmol) and 7a was a mixed-type BChE inhibitor (Ki = 1.09 µmol). Moreover, hybrid 5d and 7c could penetrate the CNS.

• MeSH
• cholinesterasové inhibitory chemie   farmakologie   MeSH
• hematoencefalická bariéra účinky léků   MeSH
• kinetika MeSH
• kumariny chemie   farmakologie   MeSH
• lidé MeSH
• molekulární modely MeSH
• permeabilita účinky léků   MeSH
• simulace molekulového dockingu MeSH
• takrin chemie   farmakologie   MeSH
• thiomočovina chemie   farmakologie   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Multi-target drug discovery is one of the most followed approaches in the active central nervous system (CNS) therapeutic area, especially in the search for new drugs against Alzheimer's disease (AD). This is because innovative multi-target-directed ligands (MTDLs) could more adequately address the complexity of this pathological condition. In a continuation of our efforts aimed at a new series of anti-AD MTDLs, we combined the structural features of the cholinesterase inhibitor drug tacrine with that of resveratrol, which is known for its purported antioxidant and anti-neuroinflammatory activities. The most interesting hybrid compounds (5, 8, 9 and 12) inhibited human acetylcholinesterase at micromolar concentrations and effectively modulated Aβ self-aggregation in vitro. In addition, 12 showed intriguing anti-inflammatory and immuno-modulatory properties in neuronal and glial AD cell models. Importantly, the MTDL profile is accompanied by high-predicted blood-brain barrier permeability, and low cytotoxicity on primary neurons.

• MeSH
• acetylcholinesterasa metabolismus   MeSH
• Alzheimerova nemoc farmakoterapie   metabolismus   MeSH
• amyloidní beta-protein chemie   MeSH
• antioxidancia chemie   metabolismus   farmakologie   terapeutické užití   MeSH
• butyrylcholinesterasa metabolismus   MeSH
• cholinesterasové inhibitory chemie   metabolismus   farmakologie   terapeutické užití   MeSH
• cílená molekulární terapie * MeSH
• hematoencefalická bariéra metabolismus   MeSH
• játra účinky léků   MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• ligandy MeSH
• neuroprotektivní látky chemie   farmakologie   terapeutické užití   MeSH
• peptidové fragmenty chemie   MeSH
• proteinové agregáty účinky léků   MeSH
• racionální návrh léčiv * MeSH
• stilbeny chemie   MeSH
• takrin chemie   metabolismus   farmakologie   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Reversible acetylcholinesterase inhibitors are used in Alzheimer disease therapy. However, tacrine and its derivatives have severe side effects. Derivatives of the tacrine analogue 7-methoxytacrine (MEOTA) are less toxic. METHODS: We evaluated new derivatives of 7-MEOTA (2 homodimers linked by 2 C4-C5 chains and 5 N-alkylated C4-C8 side chain derivatives) in vitro, using the rat hippocampal choline transporter CHT1. RESULTS: Some derivatives were effective inhibitors of rat acetylcholinesterase and comparable with 7-MEOTA. All derivatives were able to inhibit CHT1, probably via quaternary ammonium, and this interaction could be involved in the enhancement of their detrimental side effects and/or in the attenuation of their promising effects. Under conditions of disrupted lipid rafts, the unfavorable effects of some derivatives were weakened. Only tacrine was probably able to stereospecifically interact with the naturally occurring amyloid-β isoform and to simultaneously stimulate CHT1. Some derivatives, when coincubated with amyloid β, did not influence CHT1. All derivatives also increased the fluidity of the cortical membranes. CONCLUSION: The N-alkylated derivative of 7-MEOTA bearing from C4 side chains appears to be the most promising compound and should be evaluated in future in vivo research.

• MeSH
• alkylace MeSH
• amyloidní beta-protein účinky léků   MeSH
• cholesterol metabolismus   MeSH
• cholin metabolismus   MeSH
• cholinesterasové inhibitory chemická syntéza   farmakologie   MeSH
• fluidita membrány účinky léků   MeSH
• hipokampus účinky léků   metabolismus   MeSH
• krysa rodu rattus MeSH
• kvartérní amoniové sloučeniny chemie   farmakologie   MeSH
• membránové mikrodomény účinky léků   MeSH
• mozková kůra účinky léků   MeSH
• potkani Wistar MeSH
• proteiny přenášející kationty účinky léků   MeSH
• stereoizomerie MeSH
• synaptozomy účinky léků   metabolismus   MeSH
• takrin analogy a deriváty   chemická syntéza   farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Tacrine (THA), the first clinically effective acetylcholinesterase (AChE) inhibitor and the first approved drug for the treatment of Alzheimer's disease (AD), was withdrawn from the market due to its side effects, particularly its hepatotoxicity. Nowadays, THA serves as a valuable scaffold for the design of novel agents potentially applicable for AD treatment. One such compound, namely 7-methoxytacrine (7-MEOTA), exhibits an intriguing profile, having suppressed hepatotoxicity and concomitantly retaining AChE inhibition properties. Another interesting class of AChE inhibitors represents Huprines, designed by merging two fragments of the known AChE inhibitors-THA and (-)-huperzine A. Several members of this compound family are more potent human AChE inhibitors than the parent compounds. The most promising are so-called huprines X and Y. Here, we report the design, synthesis, biological evaluation, and in silico studies of 2-methoxyhuprine that amalgamates structural features of 7-MEOTA and huprine Y in one molecule.

• MeSH
• acetylcholinesterasa MeSH
• aktivace enzymů účinky léků   MeSH
• Alzheimerova nemoc farmakoterapie   MeSH
• aminochinoliny chemická syntéza   chemie   farmakologie   MeSH
• butyrylcholinesterasa MeSH
• cholinesterasové inhibitory chemie   farmakologie   MeSH
• hematoencefalická bariéra metabolismus   MeSH
• heterocyklické sloučeniny tetra- a více cyklické chemie   farmakologie   MeSH
• hydrolýza MeSH
• inhibiční koncentrace 50 MeSH
• katalytická doména MeSH
• lidé MeSH
• molekulární konformace MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• objevování léků * MeSH
• permeabilita MeSH
• racionální návrh léčiv MeSH
• takrin analogy a deriváty   chemie   farmakologie   MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• viabilita buněk účinky léků   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder. Several hallmarks such as β-amyloid (Aβ) aggregation underlying amyloid plaque formation, τ-hyperphosphorylation leading to production of neurofibrillary tangles, and decline in the number of cholinergic neurons appear to be fundamental in the pathophysiology of the disease. Other evidence points also to the involvement of oxidative stress, biometal dyshomeostasis, inflammation, and cell cycle regulatory failure. Taking into account such premises, many attractive targets for the development of anti-AD drugs have emerged. Specifically, the multifactorial nature of AD calls for multi-target-directed ligands (MTDLs) which can be beneficial by providing interactions with multiple targets. Tacrine (THA), the first clinically effective acetylcholinesterase inhibitor, was approved for the treatment of mild to moderate AD. Unfortunately, frequent adverse effects including peripheral cholinergic effects and hepatotoxicity limited its therapeutic potential. Based on the numerous biological systems involved in AD progression, this review covers THA-incorporated hybrids possessing a neuroprotective profile. In particular, it focuses on THA hybrids capable of scavenging reactive oxygen species (ROS), and derivatives which reduce the formation of Aβ-plaques either directly by confronting the Aβ1-42 selfaggregation process or indirectly by inhibiting the BACE-1 enzyme or AChE-induced Aβ1-40 aggregation. Particular interest is also addressed to THA hybrids with suppressed hepatotoxicity.

• MeSH
• Alzheimerova nemoc farmakoterapie   metabolismus   MeSH
• lidé MeSH
• neuroprotektivní látky chemická syntéza   chemie   terapeutické užití   MeSH
• takrin analogy a deriváty   chemie   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

A novel series of acridine-coumarin hybrids was synthesized and biologically evaluated for their potential inhibitory effect on both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The newly synthesized derivatives 9a-d have shown higher activity against human AChE (hAChE) compared with 7-MEOTA as the standard drug. Among them derivative 9b exhibited the most potent acetylcholinesterase inhibitory activity, with an IC50 value of 5.85μM compared with 7-MEOTA (IC50=15μM). Molecular modelling studies were performed to predict the binding modes of compounds 9b, 9c and 9f with hAChE/hBuChE.

• MeSH
• acetylcholinesterasa chemie   metabolismus   MeSH
• akridiny chemická syntéza   chemie   metabolismus   farmakologie   MeSH
• cholinesterasové inhibitory chemická syntéza   chemie   metabolismus   farmakologie   MeSH
• inhibiční koncentrace 50 MeSH
• katalytická doména MeSH
• kumariny chemie   MeSH
• lidé MeSH
• simulace molekulového dockingu * MeSH
• techniky syntetické chemie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Alzheimer's disease is a multifactorial disease that is characterized mainly by Amyloid-β (A-β) deposits, cholinergic deficit and extensive metal (copper, iron)-induced oxidative stress. In this work we present details of the synthesis, antioxidant and copper-chelating properties, DNA protection study, cholinergic activity and amyloid-antiaggregation properties of new multifunctional tacrine-7-hydroxycoumarin hybrids. The mode of interaction between copper(II) and hybrids and interestingly, the reduction of Cu(II) to Cu(I) species (for complexes Cu-5e-g) were confirmed by EPR measurements. EPR spin trapping on the model Fenton reaction, using 5,5-dimethyl-1-pyrroline N-oxide (DMPO) as a spin trap, demonstrated a significantly suppressed formation of hydroxyl radicals for the Cu-5e complex in comparison with free copper(II). This suggests that compound 5e upon coordination to free copper ion prevents the Cu(II)-catalyzed decomposition of hydrogen peroxide, which in turn may alleviate oxidative stress-induced damage. Protective activity of hybrids 5c and 5e against DNA damage in a Fenton system (copper catalyzed) was found to be in excellent agreement with the EPR spin trapping study. Compound 5g was the most effective in the inhibition of acetylcholinesterase (hAChE, IC50=38nM) and compound 5b was the most potent inhibitor of butyrylcholinesterase (hBuChE, IC50=63nM). Compound 5c was the strongest inhibitor of A-β1-40 aggregation, although a significant inhibition (>50%) was detected for compounds 5b, 5d, 5e and 5g. Collectively, these results suggest that the design and investigation of multifunctional agents containing along with the acetylcholinesterase inhibitory segment also an antioxidant moiety capable of alleviating metal (copper)-induced oxidative stress, may be of importance in the treatment of Alzheimer's disease.

• MeSH
• acetylcholinesterasa chemie   MeSH
• Alzheimerova nemoc farmakoterapie   metabolismus   MeSH
• amyloidní beta-protein chemie   MeSH
• butyrylcholinesterasa chemie   MeSH
• cholinesterasové inhibitory * chemická syntéza   chemie   MeSH
• GPI-vázané proteiny chemie   MeSH
• kumariny * chemická syntéza   chemie   MeSH
• lidé MeSH
• měď chemie   MeSH
• oxidační stres * MeSH
• peptidové fragmenty chemie   MeSH
• takrin * chemická syntéza   chemie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

The adamantane moiety is the structural backbone of numerous compounds and its discovery launched a new field of chemistry studying the approaches to the synthesis as well as the physicochemical and biological properties of organic polyhedral compounds with practical application in the pharmaceutical industry. Adamantane derivatives have proven to be very potent compounds in a wide range of applications from systemic to topical therapy. This review summarizes the currently available adamantane derivatives in clinical practice (amantadine, memantine, rimantadine, tromantadine, adapalene, saxagliptin, vildagliptin), focusing on mechanisms of action, pharmacokinetics, pharmacodynamics and clinical trials. The adamantane-based compounds presented in this manuscript have been approved for a wide spectrum of indications (antivirals, antidiabetics and against Alzheimer's and Parkinson's disease). Each of the compounds proved to be of vital importance in their therapeutic indication for numerous patients worldwide. This review also considers the mechanisms of side effects to deliver a complete perspective on current treatment options.

• MeSH
• adamantan analogy a deriváty   farmakokinetika   terapeutické užití   MeSH
• Alzheimerova nemoc farmakoterapie   MeSH
• antivirové látky chemie   farmakokinetika   terapeutické užití   MeSH
• chřipka lidská farmakoterapie   MeSH
• diabetes mellitus 2. typu farmakoterapie   MeSH
• hypoglykemika chemie   farmakokinetika   terapeutické užití   MeSH
• lidé MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH