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    Wyświetlanie 1-7 z 7
    Tytuł:
    Discovery of Potential, Dual-Active Histamine H3 Receptor Ligands with Combined Antioxidant Properties
    Autorzy:
    Mika, Kamil
    Reiner-Link, David
    Kieć-Kononowicz, Katarzyna
    Stark, Holger
    Kotańska, Magdalena
    Szczepańska, Katarzyna
    Kuder, Kamil
    Opis:
    In an attempt to find new dual acting histamine H3 receptor H$_{3}$R ligands, we designed a series of compounds, structurally based on previously described in our group, a highly active and selective human histamine H3 receptor (hH$_{3}$R) ligand KSK63. As a result, 15 obtained compounds show moderate hH$_{3}$R affinity, the best being the compound 17 (H$_{3}$R K$_{i}$ = 518 nM). Docking to the histamine H$_{3}$R homology model revealed two possible binding modes, with key interactions retained in both cases. In an attempt to find possible dual acting ligands, selected compounds were tested for antioxidant properties. Compound 16 (hH$_{3}$R K$_{i}$ = 592 nM) showed the strongest antioxidant properties at the concentration of 10−4 mol/L. It significantly reduced the amount of free radicals presenting 50–60% of ascorbic acid activity in the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, as well as showed antioxidative properties in the ferric reducing antioxidant power (FRAP) assay. Despite the yet unknown antioxidation mechanism and moderate hH$_{3}$R affinity, 16 (QD13) constitutes a starting point for the search of potential dual acting H$_{3}$R ligands-promising tools for the treatment of neurological disorders associated with increased neuronal oxidative stress.
    Dostawca treści:
    Repozytorium Uniwersytetu Jagiellońskiego
    Artykuł
    Tytuł:
    Biphenylalkoxyamine Derivatives - Histamine H3 Receptor Ligands with Butyrylcholinesterase Inhibitory Activity
    Autorzy:
    Zaręba, Paula
    Olejarz-Maciej, Agnieszka
    Kieć-Kononowicz, Katarzyna
    Kaleta, Maria
    Bajda, Marek
    Stary, Dorota
    Malawska, Barbara
    Łażewska, Dorota
    Stark, Holger
    Reiner-Link, David
    Mogilski, Szczepan
    Frank, Annika
    Godyń, Justyna
    Doroz-Płonka, Agata
    Opis:
    Neurodegenerative diseases, e.g., Alzheimer’s disease (AD), are a key health problem in the aging population. The lack of effective therapy and diagnostics does not help to improve this situation. It is thought that ligands influencing multiple but interconnected targets can contribute to a desired pharmacological effect in these complex illnesses. Histamine H3 receptors (H3Rs) play an important role in the brain, influencing the release of important neurotransmitters, such as acetylcholine. Compounds blocking their activity can increase the level of these neurotransmitters. Cholinesterases (acetyl- and butyrylcholinesterase) are responsible for the hydrolysis of acetylcholine and inactivation of the neurotransmitter. Increased activity of these enzymes, especially butyrylcholinesterase (BuChE), is observed in neurodegenerative diseases. Currently, cholinesterase inhibitors: donepezil, rivastigmine and galantamine are used in the symptomatic treatment of AD. Thus, compounds simultaneously blocking H3R and inhibiting cholinesterases could be a promising treatment for AD. Herein, we describe the BuChE inhibitory activity of H3R ligands. Most of these compounds show high affinity for human H3R (Ki < 150 nM) and submicromolar inhibition of BuChE (IC50 < 1 µM). Among all the tested compounds, 19 (E153, 1-(5-([1,1′-biphenyl]-4-yloxy)pentyl)azepane) exhibited the most promising in vitro affinity for human H3R, with a Ki value of 33.9 nM, and for equine serum BuChE, with an IC50 of 590 nM. Moreover, 19 (E153) showed inhibitory activity towards human MAO B with an IC50 of 243 nM. Furthermore, in vivo studies using the Passive Avoidance Task showed that compound 19 (E153) effectively alleviated memory deficits caused by scopolamine. Taken together, these findings suggest that compound 19 can be a lead structure for developing new anti-AD agents.
    Dostawca treści:
    Repozytorium Uniwersytetu Jagiellońskiego
    Artykuł
    Tytuł:
    Cyanobiphenyls : Novel H3 receptor ligands with cholinesterase and MAO B inhibitory activity as multitarget compounds for potential treatment of Alzheimers disease
    Autorzy:
    Zaręba, Paula
    Stary, Dorota
    Frank, Annika
    Mogilski, Szczepan
    Łażewska, Dorota
    Kaleta, Maria
    Latacz, Gniewomir
    Malawska, Barbara
    Lubelska, Annamaria
    Olejarz-Maciej, Agnieszka
    Bajda, Marek
    Godyń, Justyna
    Kieć-Kononowicz, Katarzyna
    Honkisz-Orzechowska, Ewelina
    Handzlik, Jadwiga
    Reiner-Link, David
    Doroz-Płonka, Agata
    Holger Stark
    Opis:
    Alzheimer’s disease (AD) is a complex and incurable illness that requires the urgent approval of new effective drugs. However, since 2003, no new molecules have shown successful results in clinical trials, thereby making the common “one compound – one target” paradigm questionable. Recently, the multitarget-directed ligand (MTDL) approach has gained popularity, as compounds targeting at least two biological targets may be potentially more effective in treating AD. On the basis of these findings, we designed, synthesized, and evaluated through biological assays a series of derivatives of alicyclic amines linked by an alkoxy bridge to an aromatic lipophilic moiety of [1,1ʹ-biphenyl]-4-carbonitrile. The research results revealed promising biological activity of the obtained compounds toward the chosen targets involved in AD pathophysiology; the compounds showed high affinity (mostly low nanomolar range of Ki values) for human histamine H3 receptors (hH3R) and good nonselective inhibitory potency (micromolar range of IC50 values) against acetylcholinesterase from electric eel (eeAChE) and equine serum butyrylcholinesterase (eqBuChE). Moreover, micromolar/submicromolar potency against human monoamine oxidase B (hMAO B) was detected for some compounds. The study identified compound 5 as a multiple hH3R/eeAChE/eqBuChE/hMAO B ligand (5: hH3R Ki = 9.2 nM; eeAChE IC50 = 2.63 µM; eqBuChE IC50 = 1.30 µM; hMAO B IC50 = 0.60 µM). Further in vitro studies revealed that compound 5 exhibits a mixed type of eeAChE and eqBuChE inhibition, good metabolic stability, and moderate hepatotoxicity effect on HepG2 cells. Finally, compound 5 showed a beneficial effect on scopolamine-induced memory impairments, as assessed by the passive avoidance test, thus revealing the potential of this compound as a promising agent for further optimization for AD treatment.
    Dostawca treści:
    Repozytorium Uniwersytetu Jagiellońskiego
    Artykuł
    Tytuł:
    Dual targeting ligands - histamine H3 receptor ligands with monoamine oxidase B inhibitory activity - in vitro and in vivo evaluation
    Autorzy:
    Frank, Annika
    Sromek-Trzaskowska, Wioletta
    Wieczorek, Marek
    Łażewska, Dorota
    Wagner, Waldemar
    Jóźwiak-Bębenista, Marta
    Stark, Holger
    Stasiak, Anna
    Olejarz-Maciej, Agnieszka
    Siwek, Agata
    Wiktorowska-Owczarek, Anna
    Kieć-Kononowicz, Katarzyna
    Honkisz-Orzechowska, Ewelina
    Królicka, Ewelina
    Reiner-Link, David
    Doroz-Płonka, Agata
    Opis:
    The clinical symptoms of Parkinson’s disease (PD) appear when dopamine (DA) concentrations in the striatum drops to around 20%. Simultaneous inhibitory effects on histamine H$_{3}$ receptor (H$_{3}$R) and MAO B can increase DA levels in the brain. A series of compounds was designed and tested in vitro for human H$_{3}$R (h$_{3}$) affinity and inhibitory activity to human MAO B (hMAO B). Results showed different activity of the compounds towards the two biological targets. Most compounds had poor affinity for h$_{3}$ (K$_{i}$ > 500 nM), but very good inhibitory potency for hMAO B (IC$_{50}$ < 50 nM). After further in vitro testing (modality of MAO B inhibition, permeability in PAMPA assay, cytotoxicity on human astrocyte cell lines), the most promising dual-acting ligand, 1-(3-(4-(tert-butyl)phenoxy)propyl)-2-methylpyrrolidine (13: hH$_{3}$R: K$_{i}$= 25 nM; hMAO B IC$_{50}$ = 4 nM) was selected for in vivo evaluation. Studies in rats of compound 13, in a dose of 3 mg/kg of body mass, confirmed its antagonistic effects for H$_{3}$R (decline in food and a water consumption), decline in MAO B activity (>90%) in rat cerebral cortex (CTX), and an increase in DA content in CTX and striatum. Moreover, compound 13 caused a slight increase in noradrenaline, but a reduction in serotonin concentration in CTX. Thus, compound 13 is a promising dual-active ligand for the potential treatment of PD although further studies are needed to confirm this.
    Dostawca treści:
    Repozytorium Uniwersytetu Jagiellońskiego
    Artykuł
    Tytuł:
    Benzophenone derivatives with histamine H3 receptor affinity and cholinesterase inhibitory potency as multitarget-directed ligands for possible therapy of Alzheimers disease
    Autorzy:
    Frank, Annika
    Stary, Dorota
    Kaleta, Maria
    Więckowska, Anna
    Kuder, Kamil
    Olejarz-Maciej, Agnieszka
    Kieć-Kononowicz, Katarzyna
    Handzlik, Jadwiga
    Reiner-Link, David
    Doroz-Płonka, Agata
    Łażewska, Dorota
    Sudoł-Tałaj, Sylwia
    Stark, Holger
    Malawska, Barbara
    Zaręba, Paula
    Mogilski, Szczepan
    Latacz, Gniewomir
    Godyń, Justyna
    Nolte, Tobias
    Bajda, Marek
    Opis:
    The multitarget-directed ligands demonstrating affinity to histamine H3 receptor and additional cholinesterase inhibitory potency represent a promising strategy for research into the effective treatment of Alzheimer’s disease. In this study, a novel series of benzophenone derivatives was designed and synthesized. Among these derivatives, we identified compound 6 with a high affinity for H3R (Ki = 8 nM) and significant inhibitory activity toward BuChE (IC$_{50}$ = 172 nM and 1.16 µM for eqBuChE and hBuChE, respectively). Further in vitro studies revealed that compound 6 (4-fluorophenyl) (4-((5-(piperidin-1-yl)pentyl)oxy)phenyl)methanone) displays moderate metabolic stability in mouse liver microsomes, good permeability with a permeability coefficient value (Pe) of 6.3 × 10$^{-6}$ cm/s, and its safety was confirmed in terms of hepatotoxicity in the HepG2 cell line. Therefore, we investigated the in vivo activity of compound 6 in the Passive Avoidance Test and the Formalin Test. While compound 6 did not show a statistically significant influence on memory and learning, it showed analgesic properties in both acute (ED50 = 20.9 mg/kg) and inflammatory (ED$_{50}$ = 17.5 mg/kg) pain.
    Dostawca treści:
    Repozytorium Uniwersytetu Jagiellońskiego
    Artykuł
      Wyświetlanie 1-7 z 7

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