NHMRC Research Fellowship (PRF): Inhibitory neurotransmitter receptors as therapeutic targets for chronic pain and anxiety disorders (2014–2018)
Abstract:
Inhibitory neurotransmission in the brain is mediated by GABA type-A receptor (GABAAR) and glycine receptor (GlyR) Cl- channels. GABAARs are important clinical targets for therapies directed at muscle relaxation, epilepsy, anxiolysis,
sedation and anaesthesia, whereas GlyRs are emerging as clinical targets for chronic pain and spasticity. Over the next five years I will capitalise on our recent innovations to develop new treatments for neurological diseases and to understand the molecular mechanisms of neurological disease. My specific objectives are as follows.
1. Develop novel analgesics targeting GlyRs. Drugs that specifically enhance currents in á3 GlyRs produce analgesia. We have developed novel compounds that specifically enhance á3 GlyR currents with nM potency and are using these as leads to develop new analgesics. 2. Develop novel anxiolytics targeting GABAARs. Drugs that modulate á2-containing GABAARs produce anxiolysis. We have developed novel compounds that specifically enhance á2 GABAARs with nM potency and are using these as leads to develop new anxiolytics. 3. Understand the mechanisms of GlyR dysfunction in human hereditary startle disease. This provides a unique opportunity to assess how synaptic dysfunction leads to behavioural outcomes. 4. Develop a neuronal `silencing receptor¿. In addition to allowing the researcher to understand the relationship between specific behaviours and electrical activity in defined neuronal circuits, this has the potential to treat human neurological disorders caused by aberrant levels of
neuronal activity. 5. Develop a novel therapeutic pharmacophore for GlyRs and GABAARs. Methods. In addition to biochemical, molecular, fluorescence imaging and electrophysiological techniques, we have developed two new
technologies for these projects: 1) a drug discovery and development pipeline and 2) a model system for characterising the physiological properties of synaptic currents mediated by known GABAAR or GlyR isoforms.
