Kaniakova M

References (6)

Title : 7-phenoxytacrine is a dually acting drug with neuroprotective efficacy in vivo - Kaniakova_2021_Biochem.Pharmacol__114460
Author(s) : Kaniakova M , Korabecny J , Holubova K , Kleteckova L , Chvojkova M , Hakenova K , Prchal L , Novak M , Dolezal R , Hepnarova V , Svobodova B , Kucera T , Lichnerova K , Krausova B , Horak M , Vales K , Soukup O
Ref : Biochemical Pharmacology , :114460 , 2021
Abstract : N-methyl-D-aspartate receptors (NMDARs) are a subclass of glutamate receptors, which play an essential role in excitatory neurotransmission, but their excessive overactivation by glutamate leads to excitotoxicity. NMDARs are hence a valid pharmacological target for the treatment of neurodegenerative disorders; however, novel drugs targeting NMDARs are often associated with specific psychotic side effects and abuse potential. Motivated by currently available treatment against neurodegenerative diseases involving the inhibitors of acetylcholinesterase (AChE) and NMDARs, administered also in combination, we developed a dually-acting compound 7-phenoxytacrine (7-PhO-THA) and evaluated its neuropsychopharmacological and drug-like properties for potential therapeutic use. Indeed, we have confirmed the dual potency of 7-PhO-THA, i.e. potent and balanced inhibition of both AChE and NMDARs. We discovered that it selectively inhibits the GluN1/GluN2B subtype of NMDARs via an ifenprodil-binding site, in addition to its voltage-dependent inhibitory effect at both GluN1/GluN2A and GluN1/GluN2B subtypes of NMDARs. Furthermore, whereas NMDA-induced lesion of the dorsal hippocampus confirmed potent anti-excitotoxic and neuroprotective efficacy, behavioral observations showed also a cholinergic component manifesting mainly in decreased hyperlocomotion. From the point of view of behavioral side effects, 7-PhO-THA manages to avoid these, notably those analogous to symptoms of schizophrenia. Thus, CNS availability and the overall behavioral profile are promising for subsequent investigation of therapeutic use.
ESTHER : Kaniakova_2021_Biochem.Pharmacol__114460
PubMedSearch : Kaniakova_2021_Biochem.Pharmacol__114460
PubMedID: 33571502

Title : Combination of Memantine and 6-Chlorotacrine as Novel Multi-Target Compound against Alzheimer's Disease - Kaniakova_2019_Curr.Alzheimer.Res_16_821
Author(s) : Kaniakova M , Nepovimova E , Kleteckova L , Skrenkova K , Holubova K , Chrienova Z , Hepnarova V , Kucera T , Kobrlova T , Vales K , Korabecny J , Soukup O , Horak M
Ref : Curr Alzheimer Res , 16 :821 , 2019
Abstract : BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia in the elderly. It is characterized as a multi-factorial disorder with a prevalent genetic component. Due to the unknown etiology, current treatment based on acetylcholinesterase (AChE) inhibitors and N-methyl-D-aspartate receptors (NMDAR) antagonist is effective only temporary. It seems that curative treatment will necessarily be complex due to the multifactorial nature of the disease. In this context, the so-called "multi-targeting" approach has been established. OBJECTIVES: The aim of this study was to develop a multi-target-directed ligand (MTDL) combining the support for the cholinergic system by inhibition of AChE and at the same time ameliorating the burden caused by glutamate excitotoxicity mediated by the NMDAR receptors. METHODS: We have applied common approaches of organic chemistry to prepare a hybrid of 6-chlorotacrine and memantine. Then, we investigated its blocking ability towards AChE and NMDRS in vitro, as well as its neuroprotective efficacy in vivo in the model of NMDA-induced lessions. We also studied cytotoxic potential of the compound and predicted the ability to cross the blood-brain barrier. RESULTS: A novel molecule formed by combination of 6-chlorotacrine and memantine proved to be a promising multipotent hybrid capable of blocking the action of AChE as well as NMDARs. The presented hybrid surpassed the AChE inhibitory activity of the parent compound 6-Cl-THA twofold. According to results it has been revealed that our novel hybrid blocks NMDARs in the same manner as memantine, potently inhibits AChE and is predicted to cross the blood-brain barrier via passive diffusion. Finally, the MTDL design strategy was indicated by in vivo results which showed that the novel 6-Cl-THA-memantine hybrid displayed a quantitatively better neuroprotective effect than the parent compound memantine. CONCLUSION: We conclude that the combination of two pharmacophores with a synergistic mechanism of action into a single molecule offers great potential for the treatment of CNS disorders associated with cognitive decline and/or excitotoxicity mediated by NMDARs.
ESTHER : Kaniakova_2019_Curr.Alzheimer.Res_16_821
PubMedSearch : Kaniakova_2019_Curr.Alzheimer.Res_16_821
PubMedID: 30819076

Title : Multi-target-directed therapeutic potential of 7-methoxytacrine-adamantylamine heterodimers in the Alzheimer's disease treatment - Gazova_2017_Biochim.Biophys.Acta.Mol.Basis.Dis_1863_607
Author(s) : Gazova Z , Soukup O , Sepsova V , Siposova K , Drtinova L , Jost P , Spilovska K , Korabecny J , Nepovimova E , Fedunova D , Horak M , Kaniakova M , Wang ZJ , Hamouda AK , Kuca K
Ref : Biochimica & Biophysica Acta Mol Basis Dis , 1863 :607 , 2017
Abstract : Alzheimer's disease (AD) is a progressive neurodegenerative disorder and currently there is no efficient treatment. The classic drug-design strategy based on the "one-molecule-one-target" paradigm was found to be ineffective in the case of multifactorial diseases like AD. A novel multi-target-directed ligand strategy based on the assumption that a single compound consisting of two or more distinct pharmacophores is able to hit multiple targets has been proposed as promising. Herein, we investigated 7-methoxytacrine - memantine heterodimers developed with respect to the multi-target-directed ligand theory. The spectroscopic, microscopic and cell culture methods were used for systematic investigation of the interference of the heterodimers with beta-secretase (BACE1) activity, Abeta peptide amyloid fibrillization (amyloid theory) and interaction with M1 subtype of muscarinic (mAChRs), nicotinic (nAChRs) acetylcholine receptors (cholinergic theory) and N-methyl-d-aspartate receptors (NMDA) (glutamatergic theory). The drug-like properties of selected compounds have been evaluated from the point of view of blood-brain barrier penetration and cell proliferation. We have confirmed the multipotent effect of novel series of compounds. They inhibited effectively Abeta peptide amyloid fibrillization and affected the BACE1 activity. Moreover, they have AChE inhibitory potency but they could not potentiate cholinergic transmission via direct interaction with cholinergic receptors. All compounds were reported to act as an antagonist of both M1 muscarinic and muscle-type nicotinic receptors. We have found that 7-methoxytacrine - memantine heterodimers are able to hit multiple targets associated with Alzheimer's disease and thus, have a potential clinical impact for slowing or blocking the neurodegenerative process related to this disease.
ESTHER : Gazova_2017_Biochim.Biophys.Acta.Mol.Basis.Dis_1863_607
PubMedSearch : Gazova_2017_Biochim.Biophys.Acta.Mol.Basis.Dis_1863_607
PubMedID: 27865910

Title : The pharmacology of tacrine at N-methyl-d-aspartate receptors - Horak_2017_Prog.Neuropsychopharmacol.Biol.Psychiatry_75_54
Author(s) : Horak M , Holubova K , Nepovimova E , Krusek J , Kaniakova M , Korabecny J , Vyklicky L , Kuca K , Stuchlik A , Ricny J , Vales K , Soukup O
Ref : Prog Neuropsychopharmacol Biological Psychiatry , 75 :54 , 2017
Abstract : The mechanism of tacrine as a precognitive drug has been considered to be complex and not fully understood. It has been reported to involve a wide spectrum of targets involving cholinergic, gabaergic, nitrinergic and glutamatergic pathways. Here, we review the effect of tacrine and its derivatives on the NMDA receptors (NMDAR) with a focus on the mechanism of action and biological consequences related to the Alzheimer's disease treatment. Our findings indicate that effect of tacrine on glutamatergic neurons is both direct and indirect. Direct NMDAR antagonistic effect is often reported by in vitro studies; however, it is achieved by high tacrine concentrations which are not likely to occur under clinical conditions. The impact on memory and behavioral testing can be ascribed to indirect effects of tacrine caused by influencing the NMDAR-mediated currents via M1 receptor activation, which leads to inhibition of Ca2+-activated potassium channels. Such inhibition prevents membrane repolarization leading to prolonged NMDAR activation and subsequently to long term potentiation. Considering these findings, we can conclude that tacrine-derivatives with dual cholinesterase and NMDARs modulating activity may represent a promising approach in the drug development for diseases associated with cognitive dysfunction, such as the Alzheimer disease.
ESTHER : Horak_2017_Prog.Neuropsychopharmacol.Biol.Psychiatry_75_54
PubMedSearch : Horak_2017_Prog.Neuropsychopharmacol.Biol.Psychiatry_75_54
PubMedID: 28089695

Title : A Resurrection of 7-MEOTA: A Comparison with Tacrine - Soukup_2013_Curr.Alzheimer.Res_10_893
Author(s) : Soukup O , Jun D , Karasova JZ , Patocka J , Musilek K , Korabecny J , Krusek J , Kaniakova M , Sepsova V , Mandikova J , Trejtnar F , Pohanka M , Drtinova L , Pavlik M , Tobin G , Kuca K
Ref : Curr Alzheimer Res , 10 :893 , 2013
Abstract : Alzheimer s disease (AD) is a progressive neurodegenerative dementia which currently represents one of the biggest threats for the human kind. The cure is still unknown and various hypotheses (cholinergic, amyloidal, oxidative, vascular etc.) are investigated in order to understand the pathophysiology of the disease and on this basis find an effective treatment. Tacrine, the first approved drug for the AD disease treatment, has been reported to be a multitargeted drug, however it was withdrawn from the market particularly due to its hepatotoxicity. Its derivative 7-methoxytacrine (7- MEOTA) probably due to the different metabolization does not exert this side effect. The aim of our study was to compare these two cholinesterase inhibitors from various, mainly cholinergic, points of view relevant for a potential AD drug. We found that 7-MEOTA does not fall behind its more well-known parent compound - tacrine. Furthermore, we found, that 7-MEOTA exerts better properties in most of the tests related to a possible AD treatment. Only the pharmacokinetics and a higher acetylcholinesterase and butyrylcholinesterase inhibitory potency would slightly give advantages to tacrine over 7-MEOTA, but concerning its lower toxicity, better antioxidant properties, interaction with muscarinic and nicotinic receptors and "safer" metabolization provide strong evidence for reconsider 7-MEOTA and its derivatives as candidate molecules for the treatment of AD.
ESTHER : Soukup_2013_Curr.Alzheimer.Res_10_893
PubMedSearch : Soukup_2013_Curr.Alzheimer.Res_10_893
PubMedID: 24093535

Title : Oxime reactivators and their in vivo and in vitro effects on nicotinic receptors - Soukup_2011_Physiol.Res_60_679
Author(s) : Soukup O , Krusek J , Kaniakova M , Kumar UK , Oz M , Jun D , Fusek J , Kuca K , Tobin G
Ref : Physiol Res , 60 :679 , 2011
Abstract : Current treatment of organophosphorus poisoning, resulting in overstimulation and desensitization of muscarinic and nicotinic receptors by acetylcholine (ACh), consists of the administration of atropine and oxime reactivators. However, no versatile oxime reactivator has been developed yet and some mortality still remains after application of standard atropine treatment, probably due to its lack of antinicotinic action. In our study, we focused on the interesting non-acetylcholinesterase property of oximes, i.e. antinicotinic effect of reactivators. Two standard reactivators (HI-6, obidoxime) and two new compounds (K027 and K203) were chosen for in vitro (patch clamp) and in vivo (nerve-evoked muscle contraction) testings. Both examinations showed antinicotinic effects of the reactivators. In vitro inhibition of acetylcholine-evoked currents by obidoxime, HI-6 and K203 was equivalent while K027 was less potent. Similar order of potency was observed by the in vivo examinations. We thus confirm previous in vitro results, which describe antinicotinic effects of oxime reactivators, and furthermore, we show in vivo antagonism of oxime reactivators exerted by the inhibition of ACh effect on the nicotinic receptor in the neuromuscular junction. Taking together, the effects of tested oxime reactivators indicate an antagonism on both embryonic and adult form of the muscle nicotinic receptors.
ESTHER : Soukup_2011_Physiol.Res_60_679
PubMedSearch : Soukup_2011_Physiol.Res_60_679
PubMedID: 21574759