title: Identification of a Novel 1,4,8-Triazaphenanthrene Derivative as a Neuroprotectant for Dopamine Neurons Vulnerable in Parkinson's Disease.
abstract: Parkinson's disease (PD) is a chronic degenerative disorder characterized by typical motor symptoms caused by the death of dopamine (DA) neurons in the midbrain and ensuing shortage of DA in the striatum, at the level of nerve terminals. No curative treatment is presently available for PD in clinical practice. In our search for neuroprotectants in PD, we generated new 1,4,8-triazaphenanthrenes by combining 6-endo-dig-cycloisomerization of propargylquinoxalines and Suzuki or Sonogashira cross-coupling reactions. Neuroprotection assessment of newly synthesized 1,4,8-triazaphenanthrenes in a PD cellular model resulted in the discovery of a new hit compound PPQ (5m). Neuroprotection by 5m was concentration-dependent and the result of a combined effect on intracellular calcium release channels and astroglial cells. Of interest, 5m also counteracted DA cell loss in a mouse model of PD, making this molecule a promising candidate for PD treatment.
authors.affiliation: BioCIS, Université Paris-Sud, CNRS, Université Paris-Saclay, 92290 Châtenay-Malabry, France.|Institut du Cerveau et de la Moelle, 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.identifier: 0000-0002-1171-205X
authors.initials: L
authors.lastname: Ferrié
authors.affiliation: Institut du Cerveau et de la Moelle, 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.
authors.forename: Blandine
authors.initials: B
authors.lastname: Séon-Méniel
authors.affiliation: Institut du Cerveau et de la Moelle, 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, 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; D000978:Antiparkinson Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002460:Cell Line; D059290:Dopaminergic Neurons / Q000187:drug effects*; D004353:Drug Evaluation, Preclinical; D006801:Humans; D020267:MPTP Poisoning / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D000978:Antiparkinson Agents; D018696:Neuroprotective Agents
keywords: Suzuki coupling reaction; medicinal chemistry; neurodegenerative diseases; phenotypic screening; primary neuronal cultures