Development and Characterization of Novel Allosteric Modulators Acting on Metabotropic Glutamate Receptors 2 and 3

Abstract

The essential roles of glutamatergic signaling in both normal and impaired cognitive functioning have caused metabotropic glutamate (mGlu) receptors to become targets of interest for the treatment of psychiatric disorders. The eight mGlu receptors are G-protein coupled receptors, which have been placed into three groups based on their sequence homology and preferred signaling pathway. Studies of the group II receptors, mGlu2 and mGlu3, have been limited by a lack of selective ligands. We used iterative, parallel, multidimensional synthesis along with pharmacologic and pharmacokinetic analyses to develop novel allosteric modulators for these targets, which act at a distinct site from where the endogenous ligand glutamate binds. These efforts led to the development of the first reported selective mGlu3 negative allosteric modulator (NAM), a series of dual mGlu2/3 NAMs, and provided the first characterization of a selective mGlu2 NAM. These compounds were then used in a series of electrophysiological and behavioral studies to reveal an unexpected role for postsynaptic mGlu3 receptors in the development of long term depression (LTD) of synaptic firing in the medial prefrontal cortex and implicate mGlu3 dysfunction as a potential cause for persistence of cued memories. Second generation mGlu2 and mGlu3 selective NAMs were then used in rodent models of depression and anxiety, reveal a potential antidepressant effect of mGlu3 NAMs. Finally, we used a candidate gene approach to look at the distribution of variants in the genes encoding for mGlu receptors in substance dependent patients and in matched controls, which uncovered a possible correlation of structural variance in mGlu1, mGlu2, and mGlu3 receptors with the development of substance dependence.