L-3,4-Dihydroxyphenylalanine (L-DOPA) is the most effective treatment for Parkinson's disease (PD), but long- term L-DOPA administration is marred by the emergence of motor complications, namely, dyskinesia and a shortening of anti-Parkinson's benefit (wearing-OFF). In collaboration with Duke colleagues Drs. Marc Caron and Raul Gainetdinov, using a dopamine-depleted dopamine transporter knockout (DDD) mouse model, we have determined that synthetic aryl 2-cyclopropylamine small molecules (ACPs, such as 4-methoxyphenyl-2- cyclopropyl amine) significantly counter the effects of Parkinson's disease (PD) in a dopamine transporter/dopamine-deficient (DDD) mouse model of PD. These compounds exhibited marked antiparkinsonian effects including restoration of gross motor control from akinesia states, even in this mouse model that lacked detectable levels of dopamine. Furthermore, we observed that DDD mice treated with aryl-2- cyclopropylamines strongly synergistically enhanced the antiparkinsonian actions of L-DOPA, significantly dose sparing L-DOPA required for complete therapeutic efficacy to levels >10-fold lower than L-DOPA alone. Preliminary evidence suggests that these compounds work by a novel dopamine-independent mechanism.
In Aim 1 we wish to determine the antiparkinsonian activity and antidyskinesia activities of lead compounds from this class in a relevant 6-hydroxydopamine-lesioned rat model of PD. Relieve from akinesia, dose-sparing benefits to L-DOPA therapy, antidyskinesia effects and antiparkinsonian benefits (ON-time) will be evaluated as compared to vehicle controls.
In Aim 2 we wish to identify the mode of action of lead compounds from this class, and to identify and validate the target of these antiparkinsonian compounds. Should these studies be successful, new molecular targets for antiparkinsonian drug development may be revealed. In addition, this work may provide insight into how existing targets may be pharmacologically targeted to benefit PD. This work will also lend support to use of the DDD mouse model to assist PD drug discovery efforts.
A research project is proposed to deduce the mode of action and target validation of a newly discovered class of small molecules that have pronounced antiparkinsonian effects in mice that have been rendered deficient in the neurotransmitter dopamine and have strong alleviation of their Parkinson's symptoms. In addition to identifying the molecular basis of their antiparkinsonian effects, we will evaluate the activity of these compounds in a widely accepted 6-hydroxydopamine-lesioned rat model of Parkinson's Disease (PD) to determine the ability of these compounds to reduce the severity of Parkinson's akinesia (lack of movement) and to determine the degree to which this compound class reduces the severity of uncontrolled movements (dyskinesias). The latter are caused as a side effect of the prime PD therapeutic levodopa, and we have recently discovered that these anti-PD compounds act synergistic with levodopa that may reduce the dyskinesia side effects. Together this work may establish new targets and therapeutic treatment for PD and associated symptoms.