Dr. Anthony P. Davenport, Clinical Pharmacology Unit, University of Cambridge
Monday 10th February, 4.00 p.m., Marlowe Lecture Theatre 1
Our research focuses on understanding the role of novel G-protein-coupled receptors(GPCRs), together with their transmitters in the human cardiovascular system and how these are altered with disease. We concentrate on Class A GPCRs as these are the targets of about half of currently available medicines with ~90 genes encoding ‘orphan’ receptors remaining in the human genome. Each orphan GPCR is a potential drug target. A number of orphan receptors have been paired with their cognate endogenous ligands, that can be targeted using established computational modelling as well as medicinal chemistry strategies, to identify selective agonists and antagonists. Our approach will be illustrated with the apelin peptides which have an emerging role in the cardiovascular system. Down-regulation of the apelin signalling pathway is associated with cardiovascular disease including heart failure and a synthetic agonist would be of benefit. A limitation of many agonists acting at GPCRs is that after stimulating G-protein pathways to elicit a physiological response. The target receptor is internalized and ‘silenced’ via the β-arrestin pathway. Our solution is to design an agonist that shows G-protein pathway bias with reduced loss of efficacy owing to receptor down-regulation that are currently being tested in first in human, proof of principle studies.