dc.date.accessioned | 2023-03-02T18:07:08Z | |
dc.date.available | 2023-03-02T18:07:08Z | |
dc.date.created | 2022-11-10T14:57:12Z | |
dc.date.issued | 2022 | |
dc.identifier.citation | Abram, Michał Jakubiec, Marcin Reeb, Katelyn Cheng, Mary Hongying Gedschold, Robin Rapacz, Anna Mogilski, Szczepan Socała, Katarzyna Nieoczym, Dorota Szafarz, Małgorzata Latacz, Gniewomir Szulczyk, Bartłomiej Kalinowska-Tłuścik, Justyna Gawel, Kinga Aurelia Esguerra, Camila Wyska, Elżbieta Müller, Christa E. Bahar, Ivet Fontana, Andréia C. K. Wlaź, Piotr Kamiński, Rafał M. Kamiński, Krzysztof . Discovery of (R)- N-Benzyl-2-(2,5-dioxopyrrolidin-1-yl)propanamide [ (R)-AS-1 ], a Novel Orally Bioavailable EAAT2 Modulator with Drug-like Properties and Potent Antiseizure Activity in Vivo. Journal of Medicinal Chemistry. 2022, 65(17), 11703-11725 | |
dc.identifier.uri | http://hdl.handle.net/10852/100597 | |
dc.description.abstract | (R)-7 [(R)-AS-1] showed broad-spectrum antiseizure activity across in vivo mouse seizure models: maximal electroshock (MES), 6 Hz (32/44 mA), acute pentylenetetrazol (PTZ), and PTZ-kindling. A remarkable separation between antiseizure activity and CNS-related adverse effects was also observed. In vitro studies with primary glia cultures and COS-7 cells expressing the glutamate transporter EAAT2 showed enhancement of glutamate uptake, revealing a stereoselective positive allosteric modulator (PAM) effect, further supported by molecular docking simulations. (R)-7 [(R)-AS-1] was not active in EAAT1 and EAAT3 assays and did not show significant off-target activity, including interactions with targets reported for marketed antiseizure drugs, indicative of a novel and unprecedented mechanism of action. Both in vivo pharmacokinetic and in vitro absorption, distribution, metabolism, excretion, toxicity (ADME-Tox) profiles confirmed the favorable drug-like potential of the compound. Thus, (R)-7 [(R)-AS-1] may be considered as the first-in-class small-molecule PAM of EAAT2 with potential for further preclinical and clinical development in epilepsy and possibly other CNS disorders. | |
dc.language | EN | |
dc.rights | Attribution 4.0 International | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | |
dc.title | Discovery of (R)- N-Benzyl-2-(2,5-dioxopyrrolidin-1-yl)propanamide [ (R)-AS-1 ], a Novel Orally Bioavailable EAAT2 Modulator with Drug-like Properties and Potent Antiseizure Activity in Vivo | |
dc.title.alternative | ENEngelskEnglishDiscovery of (R)- N-Benzyl-2-(2,5-dioxopyrrolidin-1-yl)propanamide [ (R)-AS-1 ], a Novel Orally Bioavailable EAAT2 Modulator with Drug-like Properties and Potent Antiseizure Activity in Vivo | |
dc.type | Journal article | |
dc.creator.author | Abram, Michał | |
dc.creator.author | Jakubiec, Marcin | |
dc.creator.author | Reeb, Katelyn | |
dc.creator.author | Cheng, Mary Hongying | |
dc.creator.author | Gedschold, Robin | |
dc.creator.author | Rapacz, Anna | |
dc.creator.author | Mogilski, Szczepan | |
dc.creator.author | Socała, Katarzyna | |
dc.creator.author | Nieoczym, Dorota | |
dc.creator.author | Szafarz, Małgorzata | |
dc.creator.author | Latacz, Gniewomir | |
dc.creator.author | Szulczyk, Bartłomiej | |
dc.creator.author | Kalinowska-Tłuścik, Justyna | |
dc.creator.author | Gawel, Kinga Aurelia | |
dc.creator.author | Esguerra, Camila | |
dc.creator.author | Wyska, Elżbieta | |
dc.creator.author | Müller, Christa E. | |
dc.creator.author | Bahar, Ivet | |
dc.creator.author | Fontana, Andréia C. K. | |
dc.creator.author | Wlaź, Piotr | |
dc.creator.author | Kamiński, Rafał M. | |
dc.creator.author | Kamiński, Krzysztof | |
cristin.unitcode | 185,57,0,0 | |
cristin.unitname | Norsk Senter for Molekylærmedisin | |
cristin.ispublished | true | |
cristin.fulltext | original | |
cristin.qualitycode | 2 | |
dc.identifier.cristin | 2071997 | |
dc.identifier.bibliographiccitation | info:ofi/fmt:kev:mtx:ctx&ctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=Journal of Medicinal Chemistry&rft.volume=65&rft.spage=11703&rft.date=2022 | |
dc.identifier.jtitle | Journal of Medicinal Chemistry | |
dc.identifier.volume | 65 | |
dc.identifier.issue | 17 | |
dc.identifier.startpage | 11703 | |
dc.identifier.endpage | 11725 | |
dc.identifier.doi | https://doi.org/10.1021/acs.jmedchem.2c00534 | |
dc.type.document | Tidsskriftartikkel | |
dc.type.peerreviewed | Peer reviewed | |
dc.source.issn | 0022-2623 | |
dc.type.version | PublishedVersion | |
dc.relation.project | NFR/187615 | |