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

FERRIÉ, LAURENT; ACUÑA, LEONARDO; FIGADÈRE, BRUNO; LE DOUARON, GAEL; SÉON-MÉNIEL, BLANDINE; MICHEL, PATRICK P.; SEPULVEDA-DIAZ, JULIA E.; RAISMAN-VOZARI, RITA

ACS Chemical Neuroscience

American Chemical Society

Año: 2017 vol. 8 p. 1222 - 1231

1948-7193

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.