New 6‑Aminoquinoxaline Derivatives with Neuroprotective Effect on Dopaminergic Neurons in Cellular and Animal Parkinson Disease Models

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.