Proof of concept study for developing 1-thienyl-β-carboline derivatives as IDO1 and TDO dual inhibitors to treat Parkinson's disease complicating depression

Abstract

Depressive symptoms are the most common neuropsychiatric disorders at all stages of Parkinson’s disease (PD). Imbalances of the kynurenine pathway of tryptophan metabolism have been closely linked to the pathogenesis of PD and depression. Herein, we designed and synthesized a series of 1-thienyl-β-carboline derivatives as IDO1 and TDO dual inhibitors; among them, compound CZ-17 manifested moderate inhibitory activities to IDO1 and TDO with IC₅₀ values of 0.33 and 1.78 μM, respectively. CZ-17 inhibited the kynurenine pathway of tryptophan degradation at the cellular level, and remarkably reduced the kynurenine/tryptophan ratio. CZ-17 displayed directly neuroprotective effect in corticosterone-induced PC12 neural cell injury model. In vivo experiments demonstrated that CZ-17 significantly increased dopamine and serotonin levels, improved MPTP-induced motor disability and rescued LPS-induced depressive behavior in zebrafish model. Acute toxicity tests of CZ-17 in zebrafish embryos showed no toxicity within the effective dose range. Additionally, CZ-17 displayed the potential to cross the BBB via passive diffusion according to ADMET prediction and Caco-2 permeability assay. Thus, CZ-17 may be a promising drug candidate for PD complicating depression.