Design and synthesis of novel fluorescent ligands for the Beta-3 adrenoceptor

The Beta-3 adrenoceptor (B3AR) is an attractive therapeutic target for obesity, overactive bladder (OAB) and type-2 diabetes and belongs to the G protein-coupled receptor (GPCR) superfamily. GPCRs are complex and flexible membrane-bound proteins comprising ~800 family members. The B3AR is activated by endogenous catecholamines, such as epinephrine/norephinephrine and mediates critical homeostatic processes such as lipolysis and thermogenesis. Though the B3AR was identified >40 years ago, there is much to be learnt about its pharmacology and to-date only a handful of therapeutics for OAB have been clinically approved. In particular, most desired B3AR drugs are agonists (activating the receptors), and the real time binding behaviour of these ligands is a key component of how well they stimulate target cell types such as adipocytes and smooth muscle to provide an anti-obesity or bladder relaxation effect.
Specific aims of the project will be:
1. To generate optimised computational models of the human B3AR and use these to design, synthesise and characterise a library of novel fluorescent ligands.
2. To pharmacologically characterise the new fluorescent ligands at all beta-adrenoceptor subtypes
3. To use the computational model of the human receptor to conduct a virtual screen for leads to develop novel, selective ligand scaffolds for the B3AR.
4. To apply the new multidisciplinary knowledge (structures, chemistry, pharmacology) to the development of selected leads into potent and subtype-selective ligands for the B3AR.
This chemical biology-focused project will span the disciplines of synthetic chemistry, modelling and pharmacology to increase our understanding of B3AR biology. The importance of the adrenoceptor family as prototypical GPCRs and key therapeutic targets means this project will be of direct relevance to future drug discovery efforts.