Heterocyclic Analogues of Modafinil as Novel, Atypical Dopamine Transporter Inhibitors
Autor(a) principal: | |
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Data de Publicação: | 2017 |
Outros Autores: | , , , , , , , , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNESP |
Texto Completo: | http://dx.doi.org/10.1021/acs.jmedchem.7b01313 http://hdl.handle.net/11449/220967 |
Resumo: | Modafinil is a wake promoting compound with high potential for cognitive enhancement. It is targeting the dopamine transporter (DAT) with moderate selectivity, thereby leading to reuptake inhibition and increased dopamine levels in the synaptic cleft. A series of modafinil analogues have been reported so far, but more target-specific analogues remain to be discovered. It was the aim of this study to synthesize and characterize such analogues and, indeed, a series of compounds were showing higher activities on the DAT and a higher selectivity toward DAT versus serotonin and norepinephrine transporters than modafinil. This was achieved by substituting the amide moiety by five- and six-membered aromatic heterocycles. In vitro studies indicated binding to the cocaine pocket on DAT, although molecular dynamics revealed binding different from that of cocaine. Moreover, no release of dopamine was observed, ruling out amphetamine-like effects. The absence of neurotoxicity of a representative analogue may encourage further preclinical studies of the above-mentioned compounds. |
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Heterocyclic Analogues of Modafinil as Novel, Atypical Dopamine Transporter InhibitorsModafinil is a wake promoting compound with high potential for cognitive enhancement. It is targeting the dopamine transporter (DAT) with moderate selectivity, thereby leading to reuptake inhibition and increased dopamine levels in the synaptic cleft. A series of modafinil analogues have been reported so far, but more target-specific analogues remain to be discovered. It was the aim of this study to synthesize and characterize such analogues and, indeed, a series of compounds were showing higher activities on the DAT and a higher selectivity toward DAT versus serotonin and norepinephrine transporters than modafinil. This was achieved by substituting the amide moiety by five- and six-membered aromatic heterocycles. In vitro studies indicated binding to the cocaine pocket on DAT, although molecular dynamics revealed binding different from that of cocaine. Moreover, no release of dopamine was observed, ruling out amphetamine-like effects. The absence of neurotoxicity of a representative analogue may encourage further preclinical studies of the above-mentioned compounds.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Department of Pharmaceutical Chemistry Faculty of Life Sciences University of Vienna, Althanstraße 14Ural Federal University Named after the First President of Russia B. N. Yeltsin, 19 Mira St.Department of Analytical Chemistry Faculty of Chemistry University of Vienna, Währinger Straße 38X-ray Structure Analysis Centre Faculty of Chemistry University of Vienna, Währinger Straße 38Department of Pediatrics Medical University of ViennaLaboratory of Fine Organic Chemistry Department of Chemistry and Biochemistry Faculty of Science and Technology University of Sao Paulo State, Roberto Simonsen 305Institute of Pharmacology Centre of Physiology and Pharmacology Medical University of ViennaNeuroscience Laboratory Paracelsus Medical UniversityFAPESP: 2016/10149-0University of ViennaUral Federal University Named after the First President of Russia B. N. YeltsinMedical University of ViennaUniversidade de São Paulo (USP)Paracelsus Medical UniversityKalaba, PredragAher, Nilima Y.Ilić, MarijaDragačević, VladimirWieder, MarcusMiklosi, Andras G.Zehl, MartinWackerlig, JudithRoller, AlexanderBeryozkina, TetyanaRadoman, BojanaSaroja, Sivaprakasam R.Lindner, WolfgangGonzalez, Eduardo PerezBakulev, VasiliyLeban, Johann JakobSitte, Harald H.Urban, ErnstLanger, ThierryLubec, Gert2022-04-28T19:07:07Z2022-04-28T19:07:07Z2017-11-22info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article9330-9348http://dx.doi.org/10.1021/acs.jmedchem.7b01313Journal of Medicinal Chemistry, v. 60, n. 22, p. 9330-9348, 2017.1520-48040022-2623http://hdl.handle.net/11449/22096710.1021/acs.jmedchem.7b013132-s2.0-85035011453Scopusreponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengJournal of Medicinal Chemistryinfo:eu-repo/semantics/openAccess2022-04-28T19:07:07Zoai:repositorio.unesp.br:11449/220967Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462024-08-05T22:00:54.627505Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false |
dc.title.none.fl_str_mv |
Heterocyclic Analogues of Modafinil as Novel, Atypical Dopamine Transporter Inhibitors |
title |
Heterocyclic Analogues of Modafinil as Novel, Atypical Dopamine Transporter Inhibitors |
spellingShingle |
Heterocyclic Analogues of Modafinil as Novel, Atypical Dopamine Transporter Inhibitors Kalaba, Predrag |
title_short |
Heterocyclic Analogues of Modafinil as Novel, Atypical Dopamine Transporter Inhibitors |
title_full |
Heterocyclic Analogues of Modafinil as Novel, Atypical Dopamine Transporter Inhibitors |
title_fullStr |
Heterocyclic Analogues of Modafinil as Novel, Atypical Dopamine Transporter Inhibitors |
title_full_unstemmed |
Heterocyclic Analogues of Modafinil as Novel, Atypical Dopamine Transporter Inhibitors |
title_sort |
Heterocyclic Analogues of Modafinil as Novel, Atypical Dopamine Transporter Inhibitors |
author |
Kalaba, Predrag |
author_facet |
Kalaba, Predrag Aher, Nilima Y. Ilić, Marija Dragačević, Vladimir Wieder, Marcus Miklosi, Andras G. Zehl, Martin Wackerlig, Judith Roller, Alexander Beryozkina, Tetyana Radoman, Bojana Saroja, Sivaprakasam R. Lindner, Wolfgang Gonzalez, Eduardo Perez Bakulev, Vasiliy Leban, Johann Jakob Sitte, Harald H. Urban, Ernst Langer, Thierry Lubec, Gert |
author_role |
author |
author2 |
Aher, Nilima Y. Ilić, Marija Dragačević, Vladimir Wieder, Marcus Miklosi, Andras G. Zehl, Martin Wackerlig, Judith Roller, Alexander Beryozkina, Tetyana Radoman, Bojana Saroja, Sivaprakasam R. Lindner, Wolfgang Gonzalez, Eduardo Perez Bakulev, Vasiliy Leban, Johann Jakob Sitte, Harald H. Urban, Ernst Langer, Thierry Lubec, Gert |
author2_role |
author author author author author author author author author author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
University of Vienna Ural Federal University Named after the First President of Russia B. N. Yeltsin Medical University of Vienna Universidade de São Paulo (USP) Paracelsus Medical University |
dc.contributor.author.fl_str_mv |
Kalaba, Predrag Aher, Nilima Y. Ilić, Marija Dragačević, Vladimir Wieder, Marcus Miklosi, Andras G. Zehl, Martin Wackerlig, Judith Roller, Alexander Beryozkina, Tetyana Radoman, Bojana Saroja, Sivaprakasam R. Lindner, Wolfgang Gonzalez, Eduardo Perez Bakulev, Vasiliy Leban, Johann Jakob Sitte, Harald H. Urban, Ernst Langer, Thierry Lubec, Gert |
description |
Modafinil is a wake promoting compound with high potential for cognitive enhancement. It is targeting the dopamine transporter (DAT) with moderate selectivity, thereby leading to reuptake inhibition and increased dopamine levels in the synaptic cleft. A series of modafinil analogues have been reported so far, but more target-specific analogues remain to be discovered. It was the aim of this study to synthesize and characterize such analogues and, indeed, a series of compounds were showing higher activities on the DAT and a higher selectivity toward DAT versus serotonin and norepinephrine transporters than modafinil. This was achieved by substituting the amide moiety by five- and six-membered aromatic heterocycles. In vitro studies indicated binding to the cocaine pocket on DAT, although molecular dynamics revealed binding different from that of cocaine. Moreover, no release of dopamine was observed, ruling out amphetamine-like effects. The absence of neurotoxicity of a representative analogue may encourage further preclinical studies of the above-mentioned compounds. |
publishDate |
2017 |
dc.date.none.fl_str_mv |
2017-11-22 2022-04-28T19:07:07Z 2022-04-28T19:07:07Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://dx.doi.org/10.1021/acs.jmedchem.7b01313 Journal of Medicinal Chemistry, v. 60, n. 22, p. 9330-9348, 2017. 1520-4804 0022-2623 http://hdl.handle.net/11449/220967 10.1021/acs.jmedchem.7b01313 2-s2.0-85035011453 |
url |
http://dx.doi.org/10.1021/acs.jmedchem.7b01313 http://hdl.handle.net/11449/220967 |
identifier_str_mv |
Journal of Medicinal Chemistry, v. 60, n. 22, p. 9330-9348, 2017. 1520-4804 0022-2623 10.1021/acs.jmedchem.7b01313 2-s2.0-85035011453 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Journal of Medicinal Chemistry |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
9330-9348 |
dc.source.none.fl_str_mv |
Scopus reponame:Repositório Institucional da UNESP instname:Universidade Estadual Paulista (UNESP) instacron:UNESP |
instname_str |
Universidade Estadual Paulista (UNESP) |
instacron_str |
UNESP |
institution |
UNESP |
reponame_str |
Repositório Institucional da UNESP |
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Repositório Institucional da UNESP |
repository.name.fl_str_mv |
Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP) |
repository.mail.fl_str_mv |
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1808129384033288192 |