Allosteric modulation of Class C GPCRs for CNS and metabolic disorders

Our lab is interested in the biology and therapeutic potential of targeting Class C G protein-coupled receptors (GPCRs). We are predominantly focussed on two class members: metabotropic glutamate receptor subtype 5 (mGlu5) and the calcium-sensing receptor (CaSR). mGlu5 is an exciting new target for schizophrenia, Alzheimer's disease, autism spectrum disorders and depression, whereas modulators of the CaSR are already in the clinic for hyperparathyroidism and are putative therapeutics for osteoporosis, calcium handling disorders, asthma and idiopathic pulmonary arterial hypertension. We are pursuing a novel class of therapeutics, called allosteric modulators, to selectively target these receptors. To facilitate rational drug design and discovery efforts, a better understanding of the functional consequences and structural basis of allosteric modulation is needed.

Available projects examine:
- the structural basis of Class C GPCR activation and allosteric modulation;
- the influence of dimerisation on allosteric modulator pharmacology;
- the impact of chronic vs acute exposure to allosteric modulators on mGlu5 & CaSR activity.

To test our hypotheses, we have access to a diverse allosteric modulator collection. Techniques applied may include molecular biology, high-throughput second messenger assays, primary neuronal culture, recombinant cell culture, protein chemistry, photoaffinity labelling, immunoblotting, computational modelling, medicinal chemistry and single cell imaging.