Kleteckova L

References (4)

Title : Phenoxytacrine derivatives: Low-toxicity neuroprotectants exerting affinity to ifenprodil-binding site and cholinesterase inhibition - Misiachna_2024_Eur.J.Med.Chem_266_116130
Author(s) : Misiachna A , Svobodova B , Netolicky J , Chvojkova M , Kleteckova L , Prchal L , Novak M , Hrabinova M , Kucera T , Muckova L , Moravcova Z , Karasova JZ , Pejchal J , Blazek F , Malinak D , Hakenova K , Krausova BH , Kolcheva M , Ladislav M , Korabecny J , Pahnke J , Vales K , Horak M , Soukup O
Ref : Eur Journal of Medicinal Chemistry , 266 :116130 , 2024
Abstract : Tacrine (THA), a long withdrawn drug, is still a popular scaffold used in medicinal chemistry, mainly for its good reactivity and multi-targeted effect. However, THA-associated hepatotoxicity is still an issue and must be considered in drug discovery based on the THA scaffold. Following our previously identified hit compound 7-phenoxytacrine (7-PhO-THA), we systematically explored the chemical space with 30 novel derivatives, with a focus on low hepatotoxicity, anticholinesterase action, and antagonism at the GluN1/GluN2B subtype of the NMDA receptor. Applying the down-selection process based on in vitro and in vivo pharmacokinetic data, two candidates, I-52 and II-52, selective GluN1/GluN2B inhibitors thanks to the interaction with the ifenprodil-binding site, have entered in vivo pharmacodynamic studies. Finally, compound I-52, showing only minor affinity to AChE, was identified as a lead candidate with favorable behavioral and neuroprotective effects using open-field and prepulse inhibition tests, along with scopolamine-based behavioral and NMDA-induced hippocampal lesion models. Our data show that compound I-52 exhibits low toxicity often associated with NMDA receptor ligands, and low hepatotoxicity, often related to THA-based compounds.
ESTHER : Misiachna_2024_Eur.J.Med.Chem_266_116130
PubMedSearch : Misiachna_2024_Eur.J.Med.Chem_266_116130
PubMedID: 38218127

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 : Novel tacrine-tryptophan hybrids: Multi-target directed ligands as potential treatment for Alzheimer's disease - Chalupova_2019_Eur.J.Med.Chem_168_491
Author(s) : Chalupova K , Korabecny J , Bartolini M , Monti B , Lamba D , Caliandro R , Pesaresi A , Brazzolotto X , Gastellier AJ , Nachon F , Pejchal J , Jarosova M , Hepnarova V , Jun D , Hrabinova M , Dolezal R , Karasova JZ , Mzik M , Kristofikova Z , Misik J , Muckova L , Jost P , Soukup O , Benkova M , Setnicka V , Habartova L , Chvojkova M , Kleteckova L , Vales K , Mezeiova E , Uliassi E , Valis M , Nepovimova E , Bolognesi ML , Kuca K
Ref : Eur Journal of Medicinal Chemistry , 168 :491 , 2019
Abstract : A combination of tacrine and tryptophan led to the development of a new family of heterodimers as multi-target agents with potential to treat Alzheimer's disease. Based on the in vitro biological profile, compound S-K1035 was found to be the most potent inhibitor of human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE), demonstrating balanced IC50 values of 6.3 and 9.1nM, respectively. For all the tacrine-tryptophan heterodimers, favorable inhibitory effect on hAChE as well as on hBChE was coined to the optimal spacer length ranging from five to eight carbon atoms between these two pharmacophores. S-K1035 also showed good ability to inhibit Abeta42 self-aggregation (58.6+/-5.1% at 50muM) as well as hAChE-induced Abeta40 aggregation (48.3+/-6.3% at 100muM). The X-ray crystallographic analysis of TcAChE in complex with S-K1035 pinpointed the utility of the hybridization strategy applied and the structures determined with the two K1035 enantiomers in complex with hBChE could explain the higher inhibition potency of S-K1035. Other in vitro evaluations predicted the ability of S-K1035 to cross blood-brain barrier and to exert a moderate inhibition potency against neuronal nitric oxide synthase. Based on the initial promising biochemical data and a safer in vivo toxicity compared to tacrine, S-K1035 was administered to scopolamine-treated rats being able to dose-dependently revert amnesia.
ESTHER : Chalupova_2019_Eur.J.Med.Chem_168_491
PubMedSearch : Chalupova_2019_Eur.J.Med.Chem_168_491
PubMedID: 30851693
Gene_locus related to this paper: torca-ACHE