5 research outputs found
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<sub>2/3</sub>) 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<sub>2/3</sub> 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<sub>2/3</sub> antagonist.
Further characterization of compound <b>19f</b> binding to the
human metabotropic 2 glutamate (hmGlu<sub>2</sub>) site was established
by cocrystallization of this molecule with the amino terminal domain
(ATD) of the hmGlu<sub>2</sub> 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 mGlu<sub>2</sub> 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 mGlu<sub>2</sub> IC<sub>50</sub> value