title: New 6-Aminoquinoxaline Derivatives with Neuroprotective Effect on Dopaminergic Neurons in Cellular and Animal Parkinson Disease Models.
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.
authors.affiliation: BioCIS, Université Paris-Sud, CNRS, Université Paris-Saclay , 92290 Châtenay-Malabry, France.|Institut du Cerveau et de la Moelle Epinière, Sorbonne Universités, Université Pierre et Marie Curie Paris 06, INSERM U1127, CNRS UMR7225 , 75013 Paris, France.
authors.forename: Gael
authors.initials: G
authors.lastname: Le Douaron
authors.affiliation: BioCIS, Université Paris-Sud, CNRS, Université Paris-Saclay , 92290 Châtenay-Malabry, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Ferrié
authors.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.
authors.forename: Julia E
authors.initials: JE
authors.lastname: Sepulveda-Diaz
authors.affiliation: BioCIS, Université Paris-Sud, CNRS, Université Paris-Saclay , 92290 Châtenay-Malabry, France.|Institut du Cerveau et de la Moelle Epinière, Sorbonne Universités, Université Pierre et Marie Curie Paris 06, INSERM U1127, CNRS UMR7225 , 75013 Paris, France.
authors.forename: Majid
authors.initials: M
authors.lastname: Amar
authors.affiliation: BioCIS, Université Paris-Sud, CNRS, Université Paris-Saclay , 92290 Châtenay-Malabry, France.
authors.forename: Abha
authors.initials: A
authors.lastname: Harfouche
authors.affiliation: BioCIS, Université Paris-Sud, CNRS, Université Paris-Saclay , 92290 Châtenay-Malabry, France.
authors.forename: Blandine
authors.initials: B
authors.lastname: Séon-Méniel
authors.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.
authors.forename: Rita
authors.initials: R
authors.lastname: Raisman-Vozari
authors.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.
authors.forename: Patrick P
authors.initials: PP
authors.lastname: Michel
authors.affiliation: BioCIS, Université Paris-Sud, CNRS, Université Paris-Saclay , 92290 Châtenay-Malabry, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Figadère
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000473:pathology; D005260:Female; D008297:Male; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D010300:Parkinson Disease / Q000188:drug therapy* / Q000473:pathology; D011810:Quinoxalines / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: C403606:2-aminoquinoxaline; D018696:Neuroprotective Agents; D011810:Quinoxalines