PhD student, The University of Sydney
Synthesis of P2X7R antagonists in order to distinguish binding to orthosteric and allosteric sites
The P2X7 receptor (P2X7R) is believed to be a key mediator of inflammation in the brain (neuroinflammation) by releasing pro-inflammatory molecules such as interleukin 1-B (IL-1B). There has been substantial evidence linking high levels of IL-1B to neurodegenerative and neuropsychiatric diseases such as Alzheimer's disease, Parkinson's disease, and major depressive disorder.
There has been evidence in animal studies that shows inhibiting the action of the P2X7R prevents the release of IL-1B, and as a result, can prevent or hinder the progress of the aforementioned diseases.
No P2X7R antagonists have been successfully developed which can enter the brain in order to exert an anti-inflammatory (neuroprotective) effect, which is essential for the treatment of neurodegenerative diseases of the brain. By developing a P2X7R antagonist that can enter the brain, it will be possible to verify the conclusions drawn from animal studies that the P2X7R is an essential target for the prevention of such diseases.
My research focuses on determining the features of molecules required in order to bind to the P2X7R, and subsequently developing drug-like molecules which retain these features while using tactics of the medicinal chemist to allow entry of the molecule into the brain.
Abstract: Here we report adamantyl cyanoguanidine compounds based on hybrids of the adamantyl amide scaffold reported by AstraZeneca and cyanoguanidine scaffold reported by Abbott Laboratories. Compound 27 displayed five-fold greater inhibitory potency than the lead compound 2 in both pore-formation and interleukin-1β release assays, while 35-treated mice displayed an antidepressant phenotype in behavioral studies. This SAR study provides a proof of concept for hybrid compounds, which will help in the further development of P2X7R antagonists.
Pub.: 11 Mar '17, Pinned: 28 Aug '17
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