Objective/Rationale:
The objective of the project is to identify a selective and potent antagonist for the Cav1.3 L-type calcium channel. These channels are thought to be responsible for the selective degeneration of dopaminergic neurons underlying the core motor symptoms in Parkinson’s disease. No currently available drugs are selective for this channel. The majority of the L-type calcium channels found in the brain and peripheral cardiovascular system possess a pore-forming Cav1.2 subunit. The lack of a selective antagonist is an obstacle to neuroprotection therapies in PD patients because cardiovascular side effects limit the range of doses that can be tolerated.
Project Description:
Our project will use high-throughput screening of compound libraries that span a large region of chemical space to identify novel compounds suitable for use in humans that selectively antagonize L-type calcium channels with a pore-forming Cav1.3 subunit. These compounds will then be modified using medicinal chemistry to maximize selectivity, potency and bioavailability. Candidate compounds will then be tested in cell and animal models for neuroprotective value and potential side effects.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The availability of a Cav1.3 L-type calcium channel antagonist should accelerate our efforts to stop or slow the progression of Parkinson’s disease. Forcing vulnerable dopaminergic neurons to rely upon ions other than calcium to generate electrical activity should diminish their stress level, slow their aging and increase their ability to withstand stress.
Anticipated Outcome:
It is our expectation that our drug screening effort will identify a novel Cav1.3 calcium channel antagonist that could be used to prevent or slow the progression of Parkinson’s disease.
Progress Report
In the first year, we have screened over 30,000 compounds and identified several candidates, the most promising of which has excellent selectivity for CaV1.3 channels over the cardiovascular CaV1.2 channels, good potency and good pharmacokinetics. Although we are continuing our screen, medicinal chemistry is being used to optimize our lead compound. We anticipate testing it in an animal model this year for its neuroprotective potential.
Final Outcome
Drs. Surmeier and Silverman have successfully synthesized compounds with much greater selectivity for inhibiting Cav1.3 calcium channels vs. the more widely expressed Cav1.2 channel. Further work is needed to optimize these compounds for greater potency and brain penetration, as well as to confirm effects in pre-clinical models of PD, efforts on which the two groups collaborate. MJFF is working with Drs. Surmeier and Silverman to determine appropriate next steps.