Targeting Nicotinic Receptors to Increase Dopamine Function in Parkinson's Disease

Study Rationale:
Nicotinic alpha-6-containing receptors are a specific type of nicotinic receptor (proteins that respond to chemical messengers) expressed on dopamine neurons and are important regulators of dopamine signaling. We have identified selective positive allosteric modulators (PAMs), or protein regulators, of alpha-6 containing receptors and found that PAMs have the potential to increased dopamine release, potentially offering a new approach for Parkinson's disease(PD).

Hypothesis:
This study aims to determine whether nicotinic alpha-6 PAMs will increase dopamine functions

Study Design:
A series of studies will be performed to demonstrate if PAMs increase dopamine levels. We will perform optimization (improvement) of PAMs in order to identify a compound that is effective, has a good profile and can reach the brain. Once an optimal compound is identified, we will conduct studies to evaluate its potential neuroprotective effects. Ultimately, we aim to demonstrate a functional increase in dopamine release potentially leading to neuroprotective effects.

Impact on Diagnosis/Treatment of Parkinson's Disease:
An increase in acetylcholine-induced dopamine release using alpha-6 PAMs has the potential to slow or stop neurodegeneration in PD.

Next Steps for Development:
Should this project confirm a functional increased in dopamine release, the next steps would be to accelerate this program toward an optimization program to identify therapies that can be advanced into pre-clinical development.