Synthesis and Pharmacological Characterization of C4-Disubstituted Analogs of 1<i>S</i>,2<i>S</i>,5<i>R</i>,6<i>S</i>‑2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylate: Identification of a Potent, Selective Metabotropic Glutamate Receptor Agonist and Determination of Agonist-Bound Human mGlu2 and mGlu3 Amino Terminal Domain Structures

As part of our ongoing research to identify novel agents acting at metabotropic glutamate 2 (mGlu2) and 3 (mGlu3) receptors, we have previously reported the identification of the C4_α-methyl analog of mGlu2/3 receptor agonist <b>1</b> (LY354740). This molecule, 1<i>S</i>,2<i>S</i>,4<i>R</i>,5<i>R</i>,6<i>S</i>-2-amino-4-methylbicyclo­[3.1.0]­hexane-2,6-dicarboxylate <b>2</b> (LY541850), exhibited an unexpected mGlu2 agonist/mGlu3 antagonist pharmacological profile, whereas the C4_β-methyl diastereomer (<b>3</b>) possessed dual mGlu2/3 receptor agonist activity. We have now further explored this structure–activity relationship through the preparation of cyclic and acyclic C4-disubstituted analogs of <b>1</b>, leading to the identification of C4-spirocyclopropane <b>5</b> (LY2934747), a novel, potent, and systemically bioavailable mGlu2/3 receptor agonist which exhibits both antipsychotic and analgesic properties in vivo. In addition, through the combined use of protein–ligand X-ray crystallography employing recombinant human mGlu2/3 receptor amino terminal domains, molecular modeling, and site-directed mutagenesis, a molecular basis for the observed pharmacological profile of compound <b>2</b> is proposed