Hybrid structures based on Amiridine as potential multitarget drugs for Alzheimer's disease treatment
Provider:
Czech Science Foundation
Investigator:
Jan Korabecny, Galina Makhaeva
Abstract:
Amiridine is anticholinesterase drug used in Russia for treatment of Alzheimer´s disease and a number of other neurological disorders. It is an inhibitor of AChE and BChE, it restores fatty acid and phospholipid metabolism, normalizes the physicochemical properties of membranes. However, a search in the scientific databases showed the absence of synthetic work on the preparation of amiridine derivatives. Thus, the task of the project is to create original amiridine–based multitarget molecules with an optimal esterase profile neuroprotective and diseasemodifying properties (antioxidant, anti-glutamatergic and metal-chelating activity, ability to block AChE induced aggregation of beta-amyloid, mitoprotective and microtubulo-stabilizing properties), good BBB permeability, lack of hepatotoxicity and low acute toxicity. We will take advantage of complementary approaches in organic synthesis and in vitro tests of Czech and Russian team, excellence in in silico approaches of Russian team and in vivo experience of the Czech team to reach project objectives and deliver multitargeted ligands.
Project duration:
1-January-2020–31-December-2022
Novel neuroprotective compounds based on NMDA receptor antagonism and cholinergic stimulation
Provider:
Czech Science Foundation
Investigator:
Ondrej Soukup, Martin Horak, Karel Vales
Abstract:
In this project, we would like to follow-up the proof-of-concept project no. 16-08554S, focused on the dually acting tacrine derivatives, in the preclinically-oriented project focused on 7-MEOTA and its derivatives, where we would like to investigate and understand the mechanism of interaction of such compounds with the open-channel of the NMDA receptor. We will use in vitro data of native and specifically mutated NMDA receptors, molecular docking approaches and quantitative structure-activity relationship (QSAR) approach to describe such interaction. Such investigation is giving us also a tool for designing even more effective neuroprotectants. Therefore, the candidates with the most promising pre-clinical potential showing suitable NMDA receptor inhibitory properties while preserving anti-acetylcholinesterase activity will be subjected to thorough preclinical in vivo testing in order to evaluate and verify the real neuroprotective and pro-cognitive value rising from the dual character of such compounds.
Project duration:
1-January-2020–31-December-2022
New approaches to overcome therapeutic resistance of glioblastoma multiforme: Focus on cellular senescence and cerebral organoid model
Provider:
Czech Science Foundation
Investigator:
Zdenek Hodny, Dasa Bohaciakova, Marie Vajrychova
Abstract:
Astrocytoma IV. Glioblastoma multiforme (GBM) is the most serious form of human brain cancer. Over the last 30 years, the median survival of 15 months has not changed. The main cause of this bleak state is the high resistance of GBM cells to current therapies. It is therefore necessary to develop new approaches to the study of GBM biology like developing models that better reflect the relationships between human brain tissue and tumor, using them in studying therapeutic resistance mechanisms and monitoring new drugs effective against GBM. The aim of the project is to create a model of human brain organoid with transplanted GBM (GBM / CO) to study the mechanisms of GBM radio/chemoresistance. Using modern „omic“ analyzes, we want to elucidate the role of therapy-induced cellular senescence in the modulation of GBM cell survival signaling pathways. We also want to identify new compounds with glioblastoma-specific senolytic activity by monitoring chemical libraries and to verify their efficacy in the GBM/CO model.
Project duration:
1-January-2020–31-December-2022
Specific serotonin-dopamin modulators and their potential in the model of induced psychosis
Provider:
Czech Science Foundation
Investigator:
Ondrej Soukup, Jan Korabecny
Abstract:
Current pharmacotherapy of schizophrenia is based on targeted alternations mainly of serotoninergic and dopaminergic system by the second-generation antipsychotics. Besides classic antagonism or partial agoni on dopamine D2receptors, its seems therapeutically beneficial to affect 5-HT3 receptors as well. Current antipsychotics do not show a significant effect on 5-HT3R (with the exception of clozapine), whose antagonization improves, based on research outcomes, sensorial resistance, cognitive impairment, and negative symptoms of schizophrenia. On the basis of augmentation effect of setrons we have therefore proposed and optimized a model (structure) of antipsychotics for animal testing, which could exert partial agonism on D2R, as well as antagonism on 5-HT3R.
We will validate the proposed design in vitro and by the animal model of psychosis also for a tentative clinical use in future. Beside the antipsychotic effect, which should be at ideally comparable to that of clozapine, we believe that the novel model will exert lower incidence of side effects.
Project duration:
1-January-2019–31-December-2021
The influence of experimental gastorintestinal injury and inflammation of pharmacokinetics of Alzheimer´s disease drugs
Provider:
Czech Science Foundation
Investigator:
Jan Bures, Jana Zdarova Karasova
Abstract:
To date there are no information on alteration of pharmacokinetics profile of drugs used in Alzheimer disease (AD) if patients suffer from gastrointestinal dysfunction (due to ischaemia, drug injury and/or inflammatory bowel disease). Such an alteration could be limiting for effective pharmacotherapy of AD. The goal of this project is to determine the significance of capsule enteroscopy to set absorption window of currently available AD drugs and new compound K1065 (a hybrid molecule of tacrine and trolox) in experimental pigs (in health and experimental gastrointestinal injury induced by dextran-sodium sulphate or indomethacin). The second objective is to determine the impact of currently available AD drugs and new compound K1065 on gastric myoelectric activity (as a functional basis for possible gastrointestinal side effects of these drugs). The other aim is in vivo evaluation of pharmacokinetic and anti-inflammatory properties of newly designed compound K1065 in the gastrointestinal tract.
The aim of this project is to set absorption window for pharmacokinetics and bioavailability of currently available AD drugs and new compound K1065 (a hybrid molecule of tacrine and trolox) in experimental pigs and to determine their impact on gastric myoelectric activity.
Project duration:
1-January-2018–31-December-2020
