L-DOPA is the standard treatment of Parkinson’s disease (PD) but prolonged use results in dyskinesia. D2 agonists often require L-DOPA supplementation and can cause side effects (nausea, vomiting, psychosis, compulsive behaviour). Our aim is to assess the suitability of dopamine D1 positive allosteric modulator (PAM) compounds for the Symptoms & Side Effects treatment of PD. D1 PAMs have the potential to treat the motor symptoms of PD with reduced side-effects and to improve the cognitive deficits often seen in PD.
The project will focus on proof of principle studies to demonstrate the potential of D1 PAM treatment in PD. We have a tool compound that will enable us to assess the effects of targeting D1 positive modulation in relevant pre-clinical models. The ability of this compound to potentiate the rotational activity induced by dopamine agonists or L-DOPA will be assessed in the 6-OHDA-lesioned pre-clinical model of PD. Further studies will investigate the effect of the tool compound in normal models and demonstrate engagement of the target. The pre-clinical novel object recognition model will assess whether the compound has the ability to improve cognitive function. A successful outcome from this project would indicate the potential for D1 PAM as a target for the treatment of PD.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
D1 PAMs may be used in the early stages of PD as monotherapy or as an adjunct to L-DOPA therapy as the disease progresses. D1 PAM compounds may minimize or reduce L-DOPA associated complications such as dyskinesia, by allowing the dose of L-DOPA to be reduced but without the loss of the therapeutic effects on motor symptoms. In addition, D1 PAM compounds may also improve the cognitive defects often observed in PD.
We aim to demonstrate the potential of D1 PAMs as effective treatment for PD. In this project we will assess the existing tool compound in a series of proof of principle studies, focusing on motor effects and cognition. The validation of the target would allow further activities to focus on optimization of a molecule that could be progressed into development for the treatment of PD, ultimately a more efficacious treatment for the symptoms of PD.
The present studies have demonstrated that the D1 positive allosteric modulator (PAM) tool compound potentiates the effects of amphetamine on locomotion, rearing and grooming in normal pre-clinical models. In addition, the compound is efficacious at a wide range of doses in the novel object recognition delay paradigm in normal pre-clincal models. This constitutes the first industry demonstration of the pro-cognitive effect of a D1 PAM.
The D1 PAM showed a trend to increase rotational behaviour induced by L-DOPA and amphetamine in the 6-OHDA lesioned model. However, the effects were small and did not reach statistical significance. Further investigation into optimized molecules and appropriate Parkinson’s disease models would be required in order to demonstrate potentiation.
In summary, we have shown proof of principle for D1 PAMs as potential therapeutic tools for cognitive impairment. Further work will be needed in order to fully understand the potential role of this target as a therapeutic approach for motor symptoms of Parkinson’s disease.