Investigating the Pharmacology, Dimerisation and Receptor-Dependent Toxicology of Metabotropic Glutamate Receptor 5

G protein-coupled receptors represent the largest family of druggable targets in the human genome, with over half of drugs currently on the market acting at these receptors. Metabotropic glutamate receptor 5 is one such receptor, thought to be involved in several neurological diseases such as schizophrenia, anxiety, and depression as well as many neurodegenerative disorders. Allosteric modulators, ligands which act at a site topographically different from that of the endogenous ligand, have shown promise in overcoming many of the problems associated with previous drug development efforts targeting this receptor. Understanding the mechanistic action of these compounds is fundamental to driving further drug discovery, and as such the way in which compounds interact with metabotropic receptor 5 both in vitro and ex vivo is a key focus of this thesis. In this thesis, previous studies of the allosteric mechanism of action of two allosteric modulators, CDPPB and ADX-47273, are extended to the human metabotropic glutamate receptor 5 using recombinant cell lines and show that the action of these compounds is preserved across species. Furthermore, the allosteric mode of action of LSN-2814617 and VU0430644 is demonstrated and shown to be efficacy driven at both the human and rat receptor homologues. The pharmacological consequences of heterodimerisation between group I metabotropic glutamate receptors is explored using mutant receptors which constitutively dimerise. Data herein demonstrates that metabotropic glutamate receptor 1 inhibits the action of compounds acting at metabotropic glutamate receptor 5 in a non-reciprocal manner. Finally, the receptor-dependent neurotoxicity of LSN-2814617 is demonstrated in ex vivo tissue samples with chronic, high-dose administration of LSN-2814617 inducing neuronal cell death in the anterior cortex of the rodent brain. Understanding the interactions between metabotropic glutamate receptor 5, compounds acting at this receptor, and other receptors will be key in the development of compounds for progression to the clinic.