Identification of a Novel Calcium Selective Antagonist for Neuroprotection in PD

Objective/Rationale:
Nothing is known to slow or stop the progression of Parkinson’s disease. Our work and that of others suggests that antagonism of calcium channels having a Cav1.3 pore forming subunit reduces mitochondrial oxidant stress in substantia nigra dopaminergic neurons and, in so doing, increases their resistance to toxins and stress. There are no known selective antagonists of these channels, limiting the utility of current neuroprotective therapies. Our goal is to develop a promising small molecule antagonist (pyrimidine-2,4,6-trione) of Cav1.3 channels identified by a high throughput screen.

Project Description:
Although pyrimidine-2,4,6-triones have proven to selectively antagonize Cav1.3 calcium channels in heterologous expression systems, it is unclear whether they have the pharmacological properties necessary for a therapeutic agent. The aims of our investigation are intended to provide an answer to this question. Our first aim is to use medicinal chemistry to improve the potency of the molecules we have identified. Our second aim is then to determine whether these molecules are safe, effective and selective antagonists of Cav1.3 Ca2+ channels in pre-clinical dopaminergic neurons. Our third aim is to determine whether when these molecules are administered systemically, they protect dopaminergic neurons against toxins used to create pre-clinical models of PD (i.e., they are neuroprotective) without producing unwanted side-effects.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The studies to be conducted will determine whether the pyrimidine-2,4,6-triones have therapeutic potential. If they do, we will secure the additional funds to move them to an IND application to the FDA and a Phase 1 clinical trial. This would be a major step forward in the development of a safe, orally deliverable neuroprotective therapy for PD. At present, there is no such therapy.

Anticipated Outcome:
It is our expectation that a pyrimidine-2,4,6-trione derivative (or one of our backup compounds) will prove to have good brain bioavailability with oral administration in addition to selective and potent in antagonism of Cav1.3 calcium channels, leading to protection of dopaminergic neurons in toxin-based models of Parkinson’s disease. These properties will provide a strong motivation for the continued development of the drug toward a Phase 1 clinical neuroprotection trial in Parkinson’s disease.