TY - JOUR AU - Lo Giudice, Maria AU - Mihalik, Balázs AU - Turi, Zs AU - Dinnyés, András AU - Kobolák, Julianna TI - Calcilytic NPS 2143 Reduces Amyloid Secretion and Increases sAβPPα Release from PSEN1 Mutant iPSC-Derived Neurons JF - JOURNAL OF ALZHEIMER'S DISEASE J2 - J ALZHEIMERS DIS VL - 72 PY - 2019 IS - 3 SP - 885 EP - 899 PG - 15 SN - 1387-2877 DO - 10.3233/JAD-190602 UR - https://m2.mtmt.hu/api/publication/30883393 ID - 30883393 N1 - BioTalentum Ltd., Aulich L. Street 26, Gödöllő, H-2100, Hungary Molecular Animal Biotechnology Laboratory, Szent István University, Gödöllő, Hungary Cited By :7 Export Date: 8 April 2024 CODEN: JADIF Correspondence Address: Kobolák, J.; BioTalentum Ltd., Aulich L. Street 26, Hungary; email: manuscript.dinnyes@biotalentum.hu AB - Despite numerous efforts and studies over the last three decades, Alzheimer's disease (AD) remains a disorder not fully understood and incurable so far. Development of induced pluripotent stem cell (iPSC) technology to obtain terminally differentiated neurons from adult somatic cells revolutionized the study of AD, providing a powerful tool for modelling the disease and for screening candidate drugs. Indeed, iPSC reprogramming allowed generation of neurons from both sporadic and familial AD patients with the promise to recapitulate the early pathological mechanisms in vitro and to identify novel targets. Interestingly, NPS 2143, a negative allosteric modulator of the calcium sensing receptor, has been indicated as a possible therapeutic for AD. In the present study, we assessed the potential of our iPSC-based familial AD cellular model as a platform for drug testing. We found that iPSC-derived neurons respond to treatment with gamma-secretase inhibitor, modifying the physiological amyloid-beta protein precursor (A beta PP) processing and amyloid-beta (A beta) secretion. Moreover, we demonstrated the expression of calcium sensing receptor (CaSR) protein in human neurons derived from healthy and familial AD subjects. Finally, we showed that calcilytic NPS 2143 induced a changing of A beta and sA beta PP alpha secreted into conditioned media and modulation of CaSR and PSEN1 expression at the plasma membrane of AD neurons. Overall, our findings suggest that NPS 2143 affects important AD processes in a relevant in vitro system of familial AD. LA - English DB - MTMT ER - TY - GEN AU - Dinnyés, András AU - Janstova, Z AU - Mihalik, Balázs AU - Bódi-Jakus, M AU - Kobolák, Julianna TI - Human induced pluripotent stem cell based in vitro neurotoxicology model. Poster at The 20th International Congress on In Vitro Toxicology (ESTIV 2018) Berlin, Germany, 15-18 October 2018 TS - Poster at The 20th International Congress on In Vitro Toxicology (ESTIV 2018) Berlin, Germany, 15-18 October 2018 PY - 2018 UR - https://m2.mtmt.hu/api/publication/30877040 ID - 30877040 LA - English DB - MTMT ER - TY - GEN AU - Lo Giudice, Maria AU - Mihalik, Balázs AU - Kobolák, Julianna AU - Riccardi, D AU - Kemp, PJ. AU - Dinnyés, András TI - Expression of the Calcium sensing receptor (CaSR) in neuronal cultures generated from healthy and familial Alzheimer’s disease iPSCs. Poster at Federation of European Neuroscience Societies (FENS) Berlin, Germany, 7-11 July 2018 TS - Poster at Federation of European Neuroscience Societies (FENS) Berlin, Germany, 7-11 July 2018 PY - 2018 UR - https://m2.mtmt.hu/api/publication/30876967 ID - 30876967 LA - English DB - MTMT ER - TY - JOUR AU - Pálvölgyi, Adrienn AU - Moricz, K AU - Pataki, A AU - Mihalik, Balázs AU - Gigler, Gábor AU - Megyeri, K AU - Udvari, Szabolcs AU - Gacsályi, István AU - Antoni, Ferenc András TI - Loop F of the GABA(A) receptor alpha subunit governs GABA potency JF - NEUROPHARMACOLOGY J2 - NEUROPHARMACOLOGY VL - 128 PY - 2018 SP - 408 EP - 415 PG - 8 SN - 0028-3908 DO - 10.1016/j.neuropharm.2017.10.042 UR - https://m2.mtmt.hu/api/publication/27110255 ID - 27110255 N1 - Division of Preclinical Research, Egis Pharmaceuticals PLC, Budapest, Hungary Centre of Integrative Physiology, University of Edinburgh, Edinburgh, Scotland, United Kingdom Cited By :3 Export Date: 1 August 2019 CODEN: NEPHB Correspondence Address: Antoni, F.A.; Centre for Integrative Physiology, University of EdinburghUnited Kingdom; email: ferenc.antoni@ed.ac.uk Chemicals/CAS: 4 aminobutyric acid, 28805-76-7, 56-12-2; gamma-Aminobutyric Acid; Protein Subunits; Receptors, GABA-A Division of Preclinical Research, Egis Pharmaceuticals PLC, Budapest, Hungary Centre of Integrative Physiology, University of Edinburgh, Edinburgh, Scotland, United Kingdom Export Date: 15 January 2020 CODEN: NEPHB Correspondence Address: Antoni, F.A.; Centre for Integrative Physiology, University of EdinburghUnited Kingdom; email: ferenc.antoni@ed.ac.uk Division of Preclinical Research, Egis Pharmaceuticals PLC, Budapest, Hungary Centre of Integrative Physiology, University of Edinburgh, Edinburgh, Scotland, United Kingdom Cited By :3 Export Date: 8 May 2020 CODEN: NEPHB Correspondence Address: Antoni, F.A.; Centre for Integrative Physiology, University of EdinburghUnited Kingdom; email: ferenc.antoni@ed.ac.uk Chemicals/CAS: 4 aminobutyric acid, 28805-76-7, 56-12-2; gamma-Aminobutyric Acid; Protein Subunits; Receptors, GABA-A Division of Preclinical Research, Egis Pharmaceuticals PLC, Budapest, Hungary Centre of Integrative Physiology, University of Edinburgh, Edinburgh, Scotland, United Kingdom Cited By :3 Export Date: 11 June 2020 CODEN: NEPHB Correspondence Address: Antoni, F.A.; Centre for Integrative Physiology, University of EdinburghUnited Kingdom; email: ferenc.antoni@ed.ac.uk Division of Preclinical Research, Egis Pharmaceuticals PLC, Budapest, Hungary Centre of Integrative Physiology, University of Edinburgh, Edinburgh, Scotland, United Kingdom Cited By :5 Export Date: 31 May 2021 CODEN: NEPHB Correspondence Address: Antoni, F.A.; Centre for Integrative Physiology, United Kingdom; email: ferenc.antoni@ed.ac.uk Chemicals/CAS: 4 aminobutyric acid, 28805-76-7, 56-12-2; gamma-Aminobutyric Acid; Protein Subunits; Receptors, GABA-A LA - English DB - MTMT ER - TY - JOUR AU - Etherington, Lori-An AU - Mihalik, Balázs AU - Pálvölgyi, Adrienn AU - Ling, István AU - Pallagi, Katalin AU - Kertesz, Szabolcs AU - Varga, Peter AU - Gunn, Ben G AU - Brown, Adam R AU - Livesey, Matthew R AU - Monteiro, Olivia AU - Belelli, Delia AU - Barkoczy, Jozsef AU - Spedding, Michael AU - Gacsályi, István AU - Antoni, Ferenc András AU - Lambert, Jeremy J TI - Selective inhibition of extra-synaptic alpha 5-GABA(A) receptors by S44819, a new therapeutic agent JF - NEUROPHARMACOLOGY J2 - NEUROPHARMACOLOGY VL - 125 PY - 2017 SP - 353 EP - 364 PG - 12 SN - 0028-3908 DO - 10.1016/j.neuropharm.2017.08.012 UR - https://m2.mtmt.hu/api/publication/26877031 ID - 26877031 N1 - Division of Neuroscience, Medical Research Institute, Ninewells Hospital & Medical School, Dundee University, DundeeScotland DD19SY, United Kingdom Biotalentum Kft, Gödöllő, Aulich Lajos u. 262100, Hungary Egis Pharmaceuticals PLC, H1106, Budapest, Pf.100, Hungary Institut de Recherches Servier, Croissy-sur-Seine78290, France B.G.G. – Dept of Pediatrics, University of IrvineCA, United States M.R.L., F.A.A. Centre for Integrative Physiology, Deanery of Biomedical Sciences Edinburgh University ScotlandEH8 9XD, United Kingdom Cited By :8 Export Date: 1 August 2019 CODEN: NEPHB Correspondence Address: Lambert, J.J.; Division of Neuroscience, Medical Research Institute, Ninewells Hospital & Medical School, Dundee University, DundeeUnited Kingdom; email: j.j.lambert@dundee.ac.uk Chemicals/CAS: 4 aminobutyric acid, 28805-76-7, 56-12-2; flumazenil, 78755-81-4; muscimol, 2763-96-4; Flumazenil; GABA-A Receptor Agonists; GABA-A Receptor Antagonists; GABRA5 protein, human; Gabra5 protein, mouse; Gabra5 protein, rat; gamma-Aminobutyric Acid; Muscimol; Nootropic Agents; Receptors, GABA-A Division of Neuroscience, Medical Research Institute, Ninewells Hospital & Medical School, Dundee University, DundeeScotland DD19SY, United Kingdom Biotalentum Kft, Gödöllő, Aulich Lajos u. 262100, Hungary Egis Pharmaceuticals PLC, H1106, Budapest, Pf.100, Hungary Institut de Recherches Servier, Croissy-sur-Seine78290, France B.G.G. – Dept of Pediatrics, University of IrvineCA, United States M.R.L., F.A.A. Centre for Integrative Physiology, Deanery of Biomedical Sciences Edinburgh University ScotlandEH8 9XD, United Kingdom Cited By :19 Export Date: 31 May 2021 CODEN: NEPHB Correspondence Address: Lambert, J.J.; Division of Neuroscience, United Kingdom; email: j.j.lambert@dundee.ac.uk Chemicals/CAS: 4 aminobutyric acid, 28805-76-7, 56-12-2; flumazenil, 78755-81-4; muscimol, 2763-96-4; Flumazenil; GABA-A Receptor Agonists; GABA-A Receptor Antagonists; GABRA5 protein, human; Gabra5 protein, mouse; Gabra5 protein, rat; gamma-Aminobutyric Acid; Muscimol; Nootropic Agents; Receptors, GABA-A AB - In the mammalian central nervous system (CNS) GABAA receptors (GABAARs) mediate neuronal inhibition and are important therapeutic targets. GABAARs are composed of 5 subunits, drawn from 19 proteins, underpinning expression of 20–30 GABAAR subtypes. In the CNS these isoforms are heterogeneously expressed and exhibit distinct physiological and pharmacological properties. We report the discovery of S44819, a novel tricyclic oxazolo-2,3-benzodiazepine-derivative, that selectively inhibits α5-subunit-containing GABAARs (α5-GABAARs). Current α5-GABAAR inhibitors bind to the “benzodiazepine site”. However, in HEK293 cells expressing recombinant α5-GABAARs, S44819 had no effect on 3H-flumazenil binding, but displaced the GABAAR agonist 3H-muscimol and competitively inhibited the GABA-induced responses. Importantly, we reveal that the α5-subunit selectivity is uniquely governed by amino acid residues within the α-subunit F-loop, a region associated with GABA binding. In mouse hippocampal CA1 neurons, S44819 enhanced long-term potentiation (LTP), blocked a tonic current mediated by extrasynaptic α5-GABAARs, but had no effect on synaptic GABAARs. In mouse thalamic neurons, S44819 had no effect on the tonic current mediated by δ-GABAARs, or on synaptic (α1β2γ2) GABAARs. In rats, S44819 enhanced object recognition memory and reversed scopolamine-induced impairment of working memory in the eight-arm radial maze. In conclusion, S44819 is a first in class compound that uniquely acts as a potent, competitive, selective antagonist of recombinant and native α5-GABAARs. Consequently, S44819 enhances hippocampal synaptic plasticity and exhibits pro-cognitive efficacy. Given this profile, S44819 may improve cognitive function in neurodegenerative disorders and facilitate post-stroke recovery. © 2017 Elsevier Ltd LA - English DB - MTMT ER - TY - JOUR AU - Mihalik, Balázs AU - Pálvölgyi, Adrienn AU - Bogár, Ferenc AU - Megyeri, Katalin AU - Ling, István AU - Barkóczy, József AU - Bartha, Ferenc AU - Martinek, Tamás AU - Gacsályi, István AU - Antoni, Ferenc András TI - Loop-F of the alpha-subunit determines the pharmacologic profile of novel competitive inhibitors of GABA(A) receptors JF - EUROPEAN JOURNAL OF PHARMACOLOGY J2 - EUR J PHARMACOL VL - 798 PY - 2017 SP - 129 EP - 136 PG - 8 SN - 0014-2999 DO - 10.1016/j.ejphar.2017.01.033 UR - https://m2.mtmt.hu/api/publication/3193426 ID - 3193426 N1 - Funding Agency and Grant Number: Lendulet (Momentum) program of the Hungarian Academy of Sciences\n Funding text: With the exception of FBc, FBd and TM all authors were employees of Egis Pharmaceuticals PLC, Budapest, Hungary. The work of TM is supported by the Lendulet (Momentum) program of the Hungarian Academy of Sciences. We thank Dr. Patricia Machado (Les Laboratoires Servier, Suresnes, France) for helpful comments on the manuscript.\n Division of Preclinical Research, Egis Pharmaceuticals PLC, Hungary Chemical Research Division, Egis Pharmaceuticals PLC, Budapest, Hungary MTA-SZTE Supramolecular and Nanostructured Materials Research Group of HAS, University of Szeged, Hungary Department of Medical Chemistry, University of Szeged, Hungary Institute of Pharmaceutical Analysis, SZTE-MTA Lendület Foldamer Research Group, University of Szeged, Szeged, Hungary Cited By :5 Export Date: 22 May 2020 CODEN: EJPHA Correspondence Address: Antoni, F.A.Hungary; email: franzantoni@gmail.com Chemicals/CAS: bicuculline, 485-49-4; etomidate, 15301-65-2, 33125-97-2, 51919-80-3; 4 aminobutyric acid, 28805-76-7, 56-12-2; Benzodiazepines; GABA-A Receptor Antagonists; gamma-Aminobutyric Acid; Oxazoles; Protein Subunits; Receptors, GABA-A Division of Preclinical Research, Egis Pharmaceuticals PLC, Hungary Chemical Research Division, Egis Pharmaceuticals PLC, Budapest, Hungary MTA-SZTE Supramolecular and Nanostructured Materials Research Group of HAS, University of Szeged, Hungary Department of Medical Chemistry, University of Szeged, Hungary Institute of Pharmaceutical Analysis, SZTE-MTA Lendület Foldamer Research Group, University of Szeged, Szeged, Hungary Cited By :5 Export Date: 1 January 2021 CODEN: EJPHA Correspondence Address: Antoni, F.A.Hungary; email: franzantoni@gmail.com Chemicals/CAS: bicuculline, 485-49-4; etomidate, 15301-65-2, 33125-97-2, 51919-80-3; 4 aminobutyric acid, 28805-76-7, 56-12-2; Benzodiazepines; GABA-A Receptor Antagonists; gamma-Aminobutyric Acid; Oxazoles; Protein Subunits; Receptors, GABA-A Division of Preclinical Research, Egis Pharmaceuticals PLC, Hungary Chemical Research Division, Egis Pharmaceuticals PLC, Budapest, Hungary MTA-SZTE Supramolecular and Nanostructured Materials Research Group of HAS, University of Szeged, Hungary Department of Medical Chemistry, University of Szeged, Hungary Institute of Pharmaceutical Analysis, SZTE-MTA Lendület Foldamer Research Group, University of Szeged, Szeged, Hungary Cited By :5 Export Date: 31 May 2021 CODEN: EJPHA Correspondence Address: Antoni, F.A.Hungary; email: franzantoni@gmail.com Chemicals/CAS: bicuculline, 485-49-4; etomidate, 15301-65-2, 33125-97-2, 51919-80-3; 4 aminobutyric acid, 28805-76-7, 56-12-2; Benzodiazepines; GABA-A Receptor Antagonists; gamma-Aminobutyric Acid; Oxazoles; Protein Subunits; Receptors, GABA-A LA - English DB - MTMT ER - TY - CONF AU - PALVOLGYI, A AU - ETHERINGTON, L AU - Mihalik, Balázs AU - LING, I AU - PALLAGI, K AU - KERTESZ, S AU - GUNN, BG AU - BROWN, AR AU - LIVESEY, MR AU - BELELLI, D AU - BARKOCZI, J AU - VARGA, P AU - SPEDDING, M AU - GACSALY, I AU - LAMBERT, JJ AU - Antoni, Ferenc András TI - Selective targeting of extra-synaptic α5-GABAreceptors by S44819 (Egis-13529), a novel competitive GABA receptorinhibitor compound T2 - Neuroscience Meeting Planner Soc. for Neuroscience PY - 2016 UR - https://m2.mtmt.hu/api/publication/30611333 ID - 30611333 LA - English DB - MTMT ER - TY - PAT AU - Kenéz, A AU - Bertha, Ferenc AU - Barkóczy, J AU - Antoni, Ferenc András AU - Gacsályi, István AU - Mihalik, Balázs AU - Gigler, Gábor AU - Móricz , Krisztina AU - Németh, Gábor AU - Angyalné, Pataki A AU - Kapus, G L AU - Pálvölgyi, Adrienn AU - Ling, István AU - Pethő, J AU - Simig, Gyula AU - Volk, Balázs AU - Koványiné Lax, Györgyi AU - Dancsó, András TI - New dihydro-oxazinobenzodiazepine compounds, a process for their preparation and pharmaceutical compositions containing them PY - 2015 UR - https://m2.mtmt.hu/api/publication/3102671 ID - 3102671 N1 - Chem Abstr. 2015, 163, 283239; PCT/HU2015/000003 LA - English DB - MTMT ER - TY - JOUR AU - Ling, István AU - Mihalik, Balázs AU - Etherington, LA AU - Kapus, G AU - Pálvölgyi, Adrienn AU - Gigler, Gábor AU - Kertesz, S AU - Gaal, A AU - Pallagi, K AU - Kiricsi, P AU - Szabo, E AU - Szénási, Gábor AU - Papp, L AU - Hársing, László Gábor AU - Lévay, György István AU - Spedding, M AU - Lambert, JJ AU - Belelli, D AU - Barkoczy, J AU - Volk, Balázs AU - Simig, Gyula AU - Gacsályi, István AU - Antoni, Ferenc András TI - A novel GABAA alpha 5 receptor inhibitor with therapeutic potential JF - EUROPEAN JOURNAL OF PHARMACOLOGY J2 - EUR J PHARMACOL VL - 764 PY - 2015 SP - 497 EP - 507 PG - 11 SN - 0014-2999 DO - 10.1016/j.ejphar.2015.07.005 UR - https://m2.mtmt.hu/api/publication/2920540 ID - 2920540 N1 - Ling I and Mihalik B are equal first authors. AB - Novel 2,3-benzodiazepine and related isoquinoline derivatives, substituted at position 1 with a 2-benzothiophenyl moiety, were synthesized to produce compounds that potently inhibited the action of GABA on heterologously expressed GABAA receptors containing the alpha 5 subunit (GABAA alpha5), with no apparent affinity for the benzodiazepine site. Substitutions of the benzothiophene moiety at position 4 led to compounds with drug-like properties that were putative inhibitors of extra-synaptic GABAA alpha5 receptors and had substantial blood-brain barrier permeability. Initial characterization in vivo showed that 8-methyl-5-[4-(trifluoromethyl)-1-benzothiophen-2-yl]-1,9-dihydro-2H-[1,3]oxazolo [4,5-h][2,3]benzodiazepin-2-one was devoid of sedative, pro-convulsive or motor side-effects, and enhanced the performance of rats in the object recognition test. In summary, we have discovered a first-in-class GABA-site inhibitor of extra-synaptic GABAA alpha5 receptors that has promising drug-like properties and warrants further development. LA - English DB - MTMT ER - TY - JOUR AU - Székács, Inna AU - Mike-Kaszás, Nóra AU - Gróf, Pál AU - Erdelyi, K AU - Szendro, I AU - Mihalik, Balázs AU - Pataki, A AU - Antoni, Ferenc András AU - Madarász, Emilia TI - Optical waveguide lightmode spectroscopic techniques for investigating membrane-bound ion channel activities. JF - PLOS ONE J2 - PLOS ONE VL - 8 PY - 2013 IS - 12 PG - 11 SN - 1932-6203 DO - 10.1371/journal.pone.0081398 UR - https://m2.mtmt.hu/api/publication/2506863 ID - 2506863 AB - Optical waveguide lightmode spectroscopic (OWLS) techniques were probed for monitoring ion permeation through channels incorporated into artificial lipid environment. A novel sensor set-up was developed by depositing liposomes or cell-derived membrane fragments onto hydrophilic polytetrafluoroethylene (PTFE) membrane. The fibrous material of PTFE membrane could entrap lipoid vesicles and the water-filled pores provided environment for the hydrophilic domains of lipid-embedded proteins. The sensor surface was kept clean from the lipid holder PTFE membrane by a water- and ion-permeable polyethylene terephthalate (PET) mesh. The sensor set-up was tested with egg yolk lecithin liposomes containing gramicidin ion channels and with cell-derived membrane fragments enriched in GABA-gated anion channels. The method allowed monitoring the move of Na(+) and organic cations through gramicidin channels and detecting the Cl(-)-channel functions of the (alpha5beta2gamma2) GABAA receptor in the presence or absence of GABA and the competitive GABA-blocker bicuculline. LA - English DB - MTMT ER -