Promising Outcomes of Original Grant:
Our initial hypothesis was two-fold: first, that specific nicotinic (chemical messenger) receptor subtypes are involved in nervous system responses to levodopa and, second, that activation of these receptor subtypes preserve the anti-parkinsonian benefit of levodopa while reducing dyskinetic side effects. We have obtained preliminary evidence supporting our hypothesis with our short-acting compound and currently aim to repeat our initial results and determine whether administering our long-acting compound will further decrease dyskinetic activity.
Objectives for Supplemental Investigation:
Our initial study size was small and needs to be repeated so we will increase the size of the study. We will also compare differences between the short- and long-acting formulations of our novel nicotinic agonist. The number of levodopa administrations will also be increased. Levodopa will be given at the beginning of the day and at the end of each day so that we can monitor the benefit of the short-acting verses the long-acting compound formulations. We hope that increasing the duration of compound exposure will be reflected by decreased dyskinetic activity.
Importance of This Research for the Development of a New PD Therapy:
Pre-clinical evidence suggests that the pharmacological profile of our novel nicotinic agonist (drug that increases function) may restore the deficits caused by a loss of nicotinic acetylcholine (chemical messenger) receptor subunits found in Parkinson's disease and may possess therapeutic benefit as a treatment of levodopa-induced dyskinesias. This proposal is intended to extend and reinforce the pre-clinical data package supporting the utility our novel nicotinic agonist for treating levodopa-induced dyskinesia. We are unaware of any other molecules in clinical development that have a similar pharmacological profile and an existing safety and tolerability profile to test this mechanism.