New 6-Aminoquinoxaline Derivatives with Neuroprotective Effect on Dopaminergic Neurons in Cellular and Animal Parkinson Disease Models.
Identifieur interne : 000216 ( Main/Exploration ); précédent : 000215; suivant : 000217New 6-Aminoquinoxaline Derivatives with Neuroprotective Effect on Dopaminergic Neurons in Cellular and Animal Parkinson Disease Models.
Auteurs : Gael Le Douaron [France] ; Laurent Ferrié [France] ; Julia E. Sepulveda-Diaz [France] ; Majid Amar [France] ; Abha Harfouche [France] ; Blandine Séon-Méniel [France] ; Rita Raisman-Vozari [France] ; Patrick P. Michel [France] ; Bruno Figadère [France]Source :
- Journal of medicinal chemistry [ 1520-4804 ] ; 2016.
Abstract
Parkinson's disease (PD) is a neurodegenerative disorder of aging characterized by motor symptoms that result from the loss of midbrain dopamine neurons and the disruption of dopamine-mediated neurotransmission. There is currently no curative treatment for this disorder. To discover druggable neuroprotective compounds for dopamine neurons, we have designed and synthesized a second-generation of quinoxaline-derived molecules based on structure-activity relationship studies, which led previously to the discovery of our first neuroprotective brain penetrant hit compound MPAQ (5c). Neuroprotection assessment in PD cellular models of our newly synthesized quinoxaline-derived compounds has led to the selection of a better hit compound, PAQ (4c). Extensive in vitro characterization of 4c showed that its neuroprotective action is partially attributable to the activation of reticulum endoplasmic ryanodine receptor channels. Most interestingly, 4c was able to attenuate neurodegeneration in a mouse model of PD, making this compound an interesting drug candidate for the treatment of this disorder.
DOI: 10.1021/acs.jmedchem.6b00297
PubMed: 27341519
Affiliations:
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Michel</name><affiliation wicri:level="3"><nlm:affiliation>Institut du Cerveau et de la Moelle Epinière, Sorbonne Universités, Université Pierre et Marie Curie Paris 06, INSERM U1127, CNRS UMR7225 , 75013 Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Institut du Cerveau et de la Moelle Epinière, Sorbonne Universités, Université Pierre et Marie Curie Paris 06, INSERM U1127, CNRS UMR7225 , 75013 Paris</wicri:regionArea><placeName><region type="region" nuts="2">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Figadere, Bruno" sort="Figadere, Bruno" uniqKey="Figadere B" first="Bruno" last="Figadère">Bruno Figadère</name><affiliation wicri:level="4"><nlm:affiliation>BioCIS, Université Paris-Sud, CNRS, Université Paris-Saclay , 92290 Châtenay-Malabry, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>BioCIS, Université Paris-Sud, CNRS, Université Paris-Saclay , 92290 Châtenay-Malabry</wicri:regionArea><placeName><region type="region" nuts="2">Île-de-France</region><settlement type="city">Châtenay-Malabry</settlement></placeName><orgName type="university">Université Paris-Sud</orgName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2016">2016</date><idno type="RBID">pubmed:27341519</idno><idno type="pmid">27341519</idno><idno type="doi">10.1021/acs.jmedchem.6b00297</idno><idno type="wicri:Area/PubMed/Corpus">000115</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000115</idno><idno type="wicri:Area/PubMed/Curation">000115</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000115</idno><idno type="wicri:Area/PubMed/Checkpoint">000115</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">000115</idno><idno type="wicri:Area/Ncbi/Merge">001A58</idno><idno type="wicri:Area/Ncbi/Curation">001A58</idno><idno type="wicri:Area/Ncbi/Checkpoint">001A58</idno><idno type="wicri:Area/Main/Merge">000218</idno><idno type="wicri:Area/Main/Curation">000216</idno><idno type="wicri:Area/Main/Exploration">000216</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">New 6-Aminoquinoxaline Derivatives with Neuroprotective Effect on Dopaminergic Neurons in Cellular and Animal Parkinson Disease Models.</title><author><name sortKey="Le Douaron, Gael" sort="Le Douaron, Gael" uniqKey="Le Douaron G" first="Gael" last="Le Douaron">Gael Le Douaron</name><affiliation wicri:level="4"><nlm:affiliation>BioCIS, Université Paris-Sud, CNRS, Université Paris-Saclay , 92290 Châtenay-Malabry, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>BioCIS, Université Paris-Sud, CNRS, Université Paris-Saclay , 92290 Châtenay-Malabry</wicri:regionArea><placeName><region type="region" nuts="2">Île-de-France</region><settlement type="city">Châtenay-Malabry</settlement></placeName><orgName type="university">Université Paris-Sud</orgName></affiliation></author><author><name sortKey="Ferrie, Laurent" sort="Ferrie, Laurent" uniqKey="Ferrie L" first="Laurent" last="Ferrié">Laurent Ferrié</name><affiliation wicri:level="4"><nlm:affiliation>BioCIS, Université Paris-Sud, CNRS, Université Paris-Saclay , 92290 Châtenay-Malabry, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>BioCIS, Université Paris-Sud, CNRS, Université Paris-Saclay , 92290 Châtenay-Malabry</wicri:regionArea><placeName><region type="region" nuts="2">Île-de-France</region><settlement type="city">Châtenay-Malabry</settlement></placeName><orgName type="university">Université Paris-Sud</orgName></affiliation></author><author><name sortKey="Sepulveda Diaz, Julia E" sort="Sepulveda Diaz, Julia E" uniqKey="Sepulveda Diaz J" first="Julia E" last="Sepulveda-Diaz">Julia E. Sepulveda-Diaz</name><affiliation wicri:level="3"><nlm:affiliation>Institut du Cerveau et de la Moelle Epinière, Sorbonne Universités, Université Pierre et Marie Curie Paris 06, INSERM U1127, CNRS UMR7225 , 75013 Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Institut du Cerveau et de la Moelle Epinière, Sorbonne Universités, Université Pierre et Marie Curie Paris 06, INSERM U1127, CNRS UMR7225 , 75013 Paris</wicri:regionArea><placeName><region type="region" nuts="2">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Amar, Majid" sort="Amar, Majid" uniqKey="Amar M" first="Majid" last="Amar">Majid Amar</name><affiliation wicri:level="4"><nlm:affiliation>BioCIS, Université Paris-Sud, CNRS, Université Paris-Saclay , 92290 Châtenay-Malabry, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>BioCIS, Université Paris-Sud, CNRS, Université Paris-Saclay , 92290 Châtenay-Malabry</wicri:regionArea><placeName><region type="region" nuts="2">Île-de-France</region><settlement type="city">Châtenay-Malabry</settlement></placeName><orgName type="university">Université Paris-Sud</orgName></affiliation></author><author><name sortKey="Harfouche, Abha" sort="Harfouche, Abha" uniqKey="Harfouche A" first="Abha" last="Harfouche">Abha Harfouche</name><affiliation wicri:level="4"><nlm:affiliation>BioCIS, Université Paris-Sud, CNRS, Université Paris-Saclay , 92290 Châtenay-Malabry, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>BioCIS, Université Paris-Sud, CNRS, Université Paris-Saclay , 92290 Châtenay-Malabry</wicri:regionArea><placeName><region type="region" nuts="2">Île-de-France</region><settlement type="city">Châtenay-Malabry</settlement></placeName><orgName type="university">Université Paris-Sud</orgName></affiliation></author><author><name sortKey="Seon Meniel, Blandine" sort="Seon Meniel, Blandine" uniqKey="Seon Meniel B" first="Blandine" last="Séon-Méniel">Blandine Séon-Méniel</name><affiliation wicri:level="4"><nlm:affiliation>BioCIS, Université Paris-Sud, CNRS, Université Paris-Saclay , 92290 Châtenay-Malabry, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>BioCIS, Université Paris-Sud, CNRS, Université Paris-Saclay , 92290 Châtenay-Malabry</wicri:regionArea><placeName><region type="region" nuts="2">Île-de-France</region><settlement type="city">Châtenay-Malabry</settlement></placeName><orgName type="university">Université Paris-Sud</orgName></affiliation></author><author><name sortKey="Raisman Vozari, Rita" sort="Raisman Vozari, Rita" uniqKey="Raisman Vozari R" first="Rita" last="Raisman-Vozari">Rita Raisman-Vozari</name><affiliation wicri:level="3"><nlm:affiliation>Institut du Cerveau et de la Moelle Epinière, Sorbonne Universités, Université Pierre et Marie Curie Paris 06, INSERM U1127, CNRS UMR7225 , 75013 Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Institut du Cerveau et de la Moelle Epinière, Sorbonne Universités, Université Pierre et Marie Curie Paris 06, INSERM U1127, CNRS UMR7225 , 75013 Paris</wicri:regionArea><placeName><region type="region" nuts="2">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Michel, Patrick P" sort="Michel, Patrick P" uniqKey="Michel P" first="Patrick P" last="Michel">Patrick P. Michel</name><affiliation wicri:level="3"><nlm:affiliation>Institut du Cerveau et de la Moelle Epinière, Sorbonne Universités, Université Pierre et Marie Curie Paris 06, INSERM U1127, CNRS UMR7225 , 75013 Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Institut du Cerveau et de la Moelle Epinière, Sorbonne Universités, Université Pierre et Marie Curie Paris 06, INSERM U1127, CNRS UMR7225 , 75013 Paris</wicri:regionArea><placeName><region type="region" nuts="2">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Figadere, Bruno" sort="Figadere, Bruno" uniqKey="Figadere B" first="Bruno" last="Figadère">Bruno Figadère</name><affiliation wicri:level="4"><nlm:affiliation>BioCIS, Université Paris-Sud, CNRS, Université Paris-Saclay , 92290 Châtenay-Malabry, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>BioCIS, Université Paris-Sud, CNRS, Université Paris-Saclay , 92290 Châtenay-Malabry</wicri:regionArea><placeName><region type="region" nuts="2">Île-de-France</region><settlement type="city">Châtenay-Malabry</settlement></placeName><orgName type="university">Université Paris-Sud</orgName></affiliation></author></analytic><series><title level="j">Journal of medicinal chemistry</title><idno type="eISSN">1520-4804</idno><imprint><date when="2016" type="published">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Parkinson's disease (PD) is a neurodegenerative disorder of aging characterized by motor symptoms that result from the loss of midbrain dopamine neurons and the disruption of dopamine-mediated neurotransmission. There is currently no curative treatment for this disorder. To discover druggable neuroprotective compounds for dopamine neurons, we have designed and synthesized a second-generation of quinoxaline-derived molecules based on structure-activity relationship studies, which led previously to the discovery of our first neuroprotective brain penetrant hit compound MPAQ (5c). Neuroprotection assessment in PD cellular models of our newly synthesized quinoxaline-derived compounds has led to the selection of a better hit compound, PAQ (4c). Extensive in vitro characterization of 4c showed that its neuroprotective action is partially attributable to the activation of reticulum endoplasmic ryanodine receptor channels. Most interestingly, 4c was able to attenuate neurodegeneration in a mouse model of PD, making this compound an interesting drug candidate for the treatment of this disorder.</div></front></TEI><affiliations><list><country><li>France</li></country><region><li>Île-de-France</li></region><settlement><li>Châtenay-Malabry</li><li>Paris</li></settlement><orgName><li>Université Paris-Sud</li></orgName></list><tree><country name="France"><region name="Île-de-France"><name sortKey="Le Douaron, Gael" sort="Le Douaron, Gael" uniqKey="Le Douaron G" first="Gael" last="Le Douaron">Gael Le Douaron</name></region><name sortKey="Amar, Majid" sort="Amar, Majid" uniqKey="Amar M" first="Majid" last="Amar">Majid Amar</name><name sortKey="Ferrie, Laurent" sort="Ferrie, Laurent" uniqKey="Ferrie L" first="Laurent" last="Ferrié">Laurent Ferrié</name><name sortKey="Figadere, Bruno" sort="Figadere, Bruno" uniqKey="Figadere B" first="Bruno" last="Figadère">Bruno Figadère</name><name sortKey="Harfouche, Abha" sort="Harfouche, Abha" uniqKey="Harfouche A" first="Abha" last="Harfouche">Abha Harfouche</name><name sortKey="Michel, Patrick P" sort="Michel, Patrick P" uniqKey="Michel P" first="Patrick P" last="Michel">Patrick P. Michel</name><name sortKey="Raisman Vozari, Rita" sort="Raisman Vozari, Rita" uniqKey="Raisman Vozari R" first="Rita" last="Raisman-Vozari">Rita Raisman-Vozari</name><name sortKey="Seon Meniel, Blandine" sort="Seon Meniel, Blandine" uniqKey="Seon Meniel B" first="Blandine" last="Séon-Méniel">Blandine Séon-Méniel</name><name sortKey="Sepulveda Diaz, Julia E" sort="Sepulveda Diaz, Julia E" uniqKey="Sepulveda Diaz J" first="Julia E" last="Sepulveda-Diaz">Julia E. Sepulveda-Diaz</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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