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.

Identification of a Novel 1,4,8-Triazaphenanthrene Derivative as a Neuroprotectant for Dopamine Neurons Vulnerable in Parkinson’s Disease

“…14 We reported before that the phenyl ring located at position 3 of the quinoxaline core was essential for neuroprotection by 6-aminoquinoxalines 13 and that the lack of substituent at position 2 was apparently crucial to optimize this activity. 14 Therefore, we designed a specific convergent route for the preparation of 3-aryl-1,4,8-triazaphenanthrenes 5c, 5f, 5g, 5k-o, based on a palladiumcatalyzed Suzuki coupling reaction of aryl-boronic acids or boronate esters with 3-chloro-1,4,8-triazaphenanthrene 5i. Compound 5j was prepared from a Sonogashira cross-coupling with TMS-acetylene followed by methanolysis (Scheme 1).…”

“…Finally, we also established that when given orally, PAQ was providing protection to DA neurons and their striatal terminals in a rodent model of PD. 14 At this stage, we decided to explore the neuroprotective potential of 1,4,8-triazaphenanthrenes derived synthetically from 6-aminoquinoxalines. Indeed, we recently reported that the 6-endo-dig cycloisomerization of N-propargyl-6-aminoquinoxalines leads to the expected 1,4,8-triazaphenanthrenes in a highly regioselective manner.…”

Neurotoxicity of polychlorinated biphenyls and related organohalogens

“…The authors further demonstrated that 6-OHDA reduced the spike number and rheobase of DA neurons in acute brain slices, effects that were also reversed by RyR blockade. Furthermore, novel 6-aminoquinoxaline derivatives appear to confer neuroprotective effects on DA neurons in cellular animal models of PD that are at least partially mediated through interactions with RyRs [110]. Interestingly, blocking Ca 2+ influx did not change PCB effects on intracellular dopamine levels in a catecholaminergic cell line [87], suggesting that PCBs may be more likely affecting dopamine homeostasis by mediating dysfunction of ER Ca 2+ stores.…”

Ryanodine Receptors in Autophagy: Implications for Neurodegenerative Diseases?

“…Parkinson’s disease is characterized by a loss of dopaminergic neurons, depletion of dopamine and mitochondrial dysfunction resulting in oxidative and excitotoxic stress (Hirsch et al, 2013 ). Recently, a new compound which showed neuroprotective effects in dopaminergic neurons, was tested in a Parkinson’s disease mouse model (Le Douaron et al, 2016 ). The neuroprotective effects of this compound could be partially counteracted by dantrolene, suggesting this compound operates in part by activating RyR-mediated Ca 2+ signaling.…”