Parkinson’s is a complex brain disease caused by the gradual loss of brain cells producing the neurotransmitter dopamine, which controls movement, emotion and affect. However, treatment with the gold standard levodopa to replenish dopamine can cause motor side effects called dyskinesias. Laboratory studies suggest these dyskinesias are due to too much signaling of the D1 dopamine receptor (D1R). However, we have shown in Parkinson’s models that limiting this type of D1R activation by enhancing a different type of receptor signaling (arrestin) protects against levodopa-induced dyskinesias.
We have recently pioneered an approach that can discover small receptor-interacting molecules that can induce the arrestin signaling function of receptors. Our goal is to find a small molecule for the D1R that can be used as an add-on therapy to limit dyskinesias.
We have established methods to screen hundreds of thousands of small molecules in cellular receptor assays to identify such molecules and optimize their in vivo properties. Candidate molecules will be tested in established models to establish that arrestin signaling at D1Rs is protective of dyskinesias.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
A selective D1R/arrestin small molecule could be used in conjunction with levodopa therapy to limit or eliminate the unwanted development or persistence of dyskinesias and hence prolong the efficacy of levodopa without side effects.
Next Steps for Development:
Once identified, the D1R-targeting molecules will be thoroughly tested in various established models of PD/dyskinesia. We will optimize their in vivo time course of action and brain penetrance (PK/PD) as well as determine their potential toxicity. Ultimately, such compounds could be initially evaluated in patients with persistent levodopa-induced dyskinesias and, if effective, then tested for long-term protection.