Biased dopamine receptor agonists in the potential treatment of schizophrenia and Parkinson's disease
The dopamine D2 receptor (D2R) is a G protein-coupled receptor (GPCR) and validated target for the treatment of neuropsychiatric and neurodegenerative disorders such as schizophrenia and Parkinson’s disease, respectively. Current therapeutics used to treat these diseases ameliorate the symptoms but are often associated with clinically-limiting side-effects.
Biased agonism defines a ligand’s ability to activate a specific receptor signalling cascade. In the case of the D2R, the primary signalling events are mediated by either the beta-arrestin pathway or G protein pathway. A traditional agonist generally activates both pathways simultaneously and is therefore unbiased. Beta-arrestin biased D2R agonists have been postulated to potentially improve the symptoms of Parkinson’s disease without some of the movement disorders (e.g. dyskinesias) that are often observed with current medication. Similarly, it has been hypothesised that beta-arrestin biased D2R partial agonists can potentially improve the poorly treated negative and cognitive deficits associated with schizophrenia.
This project will focus on a lead compound identified as part of a broader research program, and will investigate systematic structural modifications to this ligand, and subsequent pharmacological evaluations to elucidate the molecular determinants that engender biased agonism. Target compounds exhibiting the desired biased agonism profile will be further evaluated in disease-relevant assays.
Research Placement
Undertake a placement of a defined period in an external institution, either domestic or international, gaining experience in a different research environment that will augment your PhD.