The novel small-molecule psychomotor stabilizer, IRL790, is currently in clinical trial for treatment of levodopa-induced dyskinesia and psychosis in patients with Parkinson disease. Here, we used naïve mice to investigate the effects of acute systemic administration of IRL790 on protein levels and phosphorylation states of proteins relevant for synaptic plasticity and transmission. IRL790 increased pro-brain-derived neurotrophic factor protein levels and phosphorylation at Ser1303 of the N-methyl-D-aspartate (NMDA) subtype 2B glutamate receptor (NR2B) in prefrontal cortex. IRL790 also increased the phosphorylation states at Ser19, Ser31, and Ser40, respectively, of tyrosine hydroxylase in striatum. IRL790 reduced protein levels of the NR2B receptor in striatum but not in prefrontal cortex. Taken together, we report that systemically administered IRL790 rapidly elicits changes in protein level and phosphorylation state of proteins associated with a beneficial effect on synaptic markers and neurotransmission. SIGNIFICANCE STATEMENT: The novel small-molecule psychomotor stabilizer, IRL790, is currently in clinical trial for treatment of levodopa-induced dyskinesia and psychosis in patients with Parkinson disease. In this study, we report that systemically administered IRL790 rapidly elicits changes in protein level and phosphorylation state of proteins associated with a beneficial effect on synaptic markers and neurotransmission.
Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.