Discovery of Subtype Selective Agonists of the Group II Metabotropic Glutamate Receptors

The Group II mGlu receptors, consisting of mGlu 2 and mGlu 3 subtypes, are class C G protein-coupled receptors that regulate synaptic glutamatergic transmission. They were considered as promising new targets for treating schizophrenia in the glutamatergic hypothesis. To delineate the roles of the two subtypes, small molecules capable of pharmacologically differentiating them were highly desired. However, the orthosteric ligand binding pockets of the two subtypes are nearly identical and were perceived to be further constrained by a tyrosine-arginine π-cation pair. From a serendipitous singleton (LY541850) with modest potency and selectivity, orthosteric agonists with excellent potency and high selectivity towards mGlu 2 (LY2812223) and mGlu 3 (LY2794193) subtypes were discovered. Subsequent crystallographic studies revealed a dynamic relationship of the tyrosine–arginine pair that enlarged the orthosteric pocket and interacted with the subtype selective ligands in distinct modes. Synthesis, in vitro and in vivo preclinical characterization of these compounds as well as phase 1 clinical data of LY2812223 (via its prodrug LY2979165) are summarized in this chapter.