Research highlights and societal impact

Our diverse research endeavours in drug discovery and development have resulted in the generation of several series of diverse molecular entities that target biomarkers associated with brain disease. We have generated a number of lead series which have been protected by patent registration by the University of Sydney with successful commercialisation outcomes achieved for one of these series.

Over the last two decades there has been increasing evidence of a strong relationship between depression and immunological dysfunction in depressed patients. Excessive secretion of cytokines, such as interleukin-1b (IL-1b), and tumour necrosis factor-a (TNF-a) is increasingly recognised as a potential cause of depression. The purinergic P2X7 receptor modulates the maturation and release of cytokines such as IL-1b in macrophages and microglia and is involved in inflammatory and neurodegenerative mechanisms. This suggests that the P2X7R could play a role in the pathophysiology of depression and that blockade of the P2X7R might result in antidepressant-like properties.

To date, only a few classes of drug-like molecules are known to interact with the P2X7R. We have developed a library of small polycyclic scaffolds with varying polycyclic hydrocarbon and aromatic segments, which are currently the subject of pharmacological studies in order to evaluate their antidepressant potential.

In addition the recognition that microglial activation is closely linked to the pathophysiology of brain disease has made the Translator Protein (18 kDa) TSPO an important therapeutic and diagnostic target. We investigated the structure-activity profile of molecular probes based on pyrazolopyrimidines and determined parameters required for maintaining high binding affinity based on the existing pharmacophore model. We have further refined this model by investigating the effects on nitrogen substitution within the heterocyclic scaffold. Although this is not considered in the current pharmacophore model it has great impact on binding affinity of these molecules and potential therapeutic outcomes.