Discovery of (1 S ,2 R ,3 S ,4 S ,5 R ,6 R )-2-Amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid Hydrochloride (LY3020371·HCl): A Potent, Metabotropic Glutamate 2/3 Receptor Antagonist with Antidepressant-Like Activity
As part of our ongoing efforts to identify novel ligands for the metabotropic glutamate 2 and 3 (mGlu 2/3 ) receptors, we have incorporated substitution at the C3 and C4 positions of the (1S,2R,5R,6R)-2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid scaffold to generate mGlu 2/3 antagonists. Exploration of this structure–activity relationship (SAR) led to the identification of (1S,2R,3S,4S,5R,6R)-2-amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid hydrochloride (LY3020371·HCl, 19f), a potent, selective, and maximally efficacious mGlu 2/3 antagonist. Further characterization of compound 19f binding to the human metabotropic 2 glutamate (hmGlu 2 ) site was established by cocrystallization of this molecule with the amino terminal domain (ATD) of the hmGlu 2 receptor protein. Here, the resulting cocrystal structure revealed the specific ligand–protein interactions, which likely explain the high affinity of 19f for this site and support its functional mGlu 2 antagonist pharmacology. Further characterization of 19f in vivo demonstrated an antidepressant-like signature in the mouse forced-swim test (mFST) assay when brain levels of this compound exceeded the cellular mGlu 2 IC 50 value.