Abstract-Langmeed
Abstract
G protein-coupled receptors (GPCRs) are the target of 30% of marketed drugs and represent a key target class for disorders of the CNS. However, many drugs that act via GPCRs do so sub-optimally, lacking selectivity, disrupting spatial/temporal signalling or causing “on-target” mediated side effects. The past decade has seen a sea change in GPCR biology, underpinned by advances in structural biology, allosteric modulation and biased signalling. Allied with developments in technology, this is enabling the development of new therapeutic approaches to CNS disorders with high degrees of unmet medical need including Alzheimer’s and Parkinson’s disease, schizophrenia and addiction. Dr Kirstie Bennett (Heptares Therapeutics, U.K.) studies the molecular and structural basis of drug action at GPCRs; her work uses a novel thermostabilisation approach to determine co-crystal structures across all classes of GPCRs, including an understanding of the structural basis of efficacy at the adenosine A 2A receptor and of allosteric modulation at the mGlu5 receptor, both key targets for Parkinson’s disease. Dr Sophie Bradley (University of Glasgow, U.K.) investigates the translational and therapeutic potential of more selectively and specifically targeting GPCRs by allosteric modulation (e.g. the muscarinic M 1 receptor in neurodegeneration) and with biased agonism (e.g. muscarinic M 3 receptor); her studies employ state-of-the-art animal models and chemogenetic approaches. Dr Jess Nithhianatharah (Florey Institute, Australia) has pioneered the use of rodent touchscreen operant chambers to study the potential of synaptic proteins, including orphan GPCRs, as novel cognition targets in clinically translational models. Dr Chris Langmead (Monash University, Australia) has extensive experience of GPCR drug discovery for CNS disorders, notably muscarinic acetylcholine receptors in psychiatric disorders. His most recent work has focussed on targeting GPCRs in the striatum for the treatment of alcohol addiction. This symposium will draw on these cutting edge approaches (structural biology, allosteric modulation, chemogenetics, biased signalling and novel, translationally relevant animal models) that are driving development of new therapeutics targeting GPCRs for the treatment of CNS diseases.
