A Snapshot seminar hosted by the School of Physiology, Pharmacology and Neuroscience
Abstract: The G protein-coupled receptor (GPCR) family is the largest class of drug target. One challenge in GPCR drug discovery is our limited understanding of how GPCR signaling controls physiological effects and is especially relevant for receptors that have complex patterns of expression. In such cases, the therapeutic action of a drug is mediated through a receptor in one cell population, while deleterious side-effects may be mediated by the same receptor expressed in another. This is the case for the dopamine D2 receptor (D2R), a target for the treatment of schizophrenia and Parkinson’s disease, and the mu opioid receptor (MOR), a target for the treatment of pain.
I will touch on the possible advantages of a new class of drugs that act at allosteric sites on D2Rs. The next focus will be the importance of drug-binding kinetics. Faster association binding rates of antagonist antipsychotic drugs (APD) at the D2R correlate with a higher risk of extrapyramidal side effects (EPS). This correlation was proposed to be driven by APD ‘rebinding’ within a synapse, increasing concentrations of APD proximal to the D2R. We have used fluorescence correlation spectroscopy (FCS) to provide the first direct evidence of profound drug rebinding at the D2R, finding APD concentrations proximal to the receptor that are >250-fold higher than the nominally added concentration. These findings suggest that optimizing drug binding kinetics of APDs may improve their side effect risks. Furthermore, drug rebinding may profoundly influence our measurements of fundamental drug parameters with implications for drug discovery. I will finish by discussing our efforts to develop a chemo-genetic strategy to allow for the acute interrogation of the physiological consequences of GPCR activation and signaling in discrete cellular populations using the MOR as a model GPCR.
Host: Johan Alsio