Synthesis and Pharmacological Characterization of <i>C</i>4‑(Thiotriazolyl)-substituted-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylates. Identification of (1<i>R</i>,2<i>S</i>,4<i>R</i>,5<i>R</i>,6<i>R</i>)‑2-Amino-4-(1<i>H</i>‑1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid (LY2812223), a Highly Potent, Functionally Selective mGlu₂ Receptor Agonist

Identification of orthosteric mGlu_2/3 receptor agonists capable of discriminating between individual mGlu₂ and mGlu₃ subtypes has been highly challenging owing to the glutamate-site sequence homology between these proteins. Herein we detail the preparation and characterization of a series of molecules related to (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 <b>1</b> (LY354740) bearing <i>C</i>4-thiotriazole substituents. On the basis of second messenger responses in cells expressing other recombinant human mGlu_2/3 subtypes, a number of high potency and efficacy mGlu₂ receptor agonists exhibiting low potency mGlu₃ partial agonist/antagonist activity were identified. From this, (1<i>R</i>,2<i>S</i>,4<i>R</i>,5<i>R</i>,6<i>R</i>)-2-amino-4-(1<i>H</i>-1,2,4-triazol-3-ylsulfanyl)­bicyclo­[3.1.0]­hexane-2,6-dicarboxylic acid <b>14a</b> (LY2812223) was further characterized. Cocrystallization of <b>14a</b> with the amino terminal domains of hmGlu₂ and hmGlu₃ combined with site-directed mutation studies has clarified the underlying molecular basis of this unique pharmacology. Evaluation of <b>14a</b> in a rat model responsive to mGlu₂ receptor activation coupled with a measure of central drug disposition provides evidence that this molecule engages and activates central mGlu₂ receptors in vivo

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