Discovery of (1<i>S</i>,2<i>R</i>,3<i>S</i>,4<i>S</i>,5<i>R</i>,6<i>R</i>)‑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 (1<i>S</i>,2<i>R</i>,5<i>R</i>,6<i>R</i>)-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 (1<i>S</i>,2<i>R</i>,3<i>S</i>,4<i>S</i>,5<i>R</i>,6<i>R</i>)-2-amino-3-[(3,4-difluorophenyl)­sulfanylmethyl]-4-hydroxy-bicyclo­[3.1.0]­hexane-2,6-dicarboxylic acid hydrochloride (LY3020371·HCl, <b>19f</b>), a potent, selective, and maximally efficacious mGlu_2/3 antagonist. Further characterization of compound <b>19f</b> binding to the human metabotropic 2 glutamate (hmGlu₂) site was established by cocrystallization of this molecule with the amino terminal domain (ATD) of the hmGlu₂ receptor protein. The resulting cocrystal structure revealed the specific ligand–protein interactions, which likely explain the high affinity of <b>19f</b> for this site and support its functional mGlu₂ antagonist pharmacology. Further characterization of <b>19f</b> in vivo demonstrated an antidepressant-like signature in the mouse forced-swim test (mFST) assay when brain levels of this compound exceeded the cellular mGlu₂ IC₅₀ value