2. Academic Validation
  3. Synthesis and pharmacological characterization of C4-disubstituted analogs of 1S,2S,5R,6S-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

Synthesis and pharmacological characterization of C4-disubstituted analogs of 1S,2S,5R,6S-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

  • J Med Chem. 2015 Feb 26;58(4):1776-94. doi: 10.1021/jm501612y.
James A Monn 1,  Lourdes Prieto,  Lorena Taboada,  Concepcion Pedregal,  Junliang Hao,  Matt R Reinhard,  Steven S Henry,  Paul J Goldsmith,  Christopher D Beadle,  Lesley Walton,  Teresa Man,  Helene Rudyk,  Barry Clark,  David Tupper,  S Richard Baker,  Carlos Lamas,  Carlos Montero,  Alicia Marcos,  Jaime Blanco,  Mark Bures,  David K Clawson,  Shane Atwell,  Frances Lu,  Jing Wang,  Marijane Russell,  Beverly A Heinz,  Xushan Wang,  Joan H Carter,  Chuanxi Xiang,  John T Catlow,  Steven Swanson,  Helen Sanger,  Lisa M Broad,  Michael P Johnson,  Kelly L Knopp,  Rosa M A Simmons,  Bryan G Johnson,  David B Shaw,  David L McKinzie
Affiliations

Affiliation

  • 1 Discovery Chemistry Research and Technologies, ‡Quantitative Biology, §Structural Biology, ∥Drug Disposition, and ⊥Neuroscience Research, Eli Lilly and Company , Indianapolis, Indiana 46285, United States.
PMID: 25602126 DOI: 10.1021/jm501612y
Abstract

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 C4α-methyl analog of mGlu2/3 receptor agonist 1 (LY354740). This molecule, 1S,2S,4R,5R,6S-2-amino-4-methylbicyclo[3.1.0]hexane-2,6-dicarboxylate 2 (LY541850), exhibited an unexpected mGlu2 agonist/mGlu3 antagonist pharmacological profile, whereas the C4β-methyl diastereomer (3) 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 1, leading to the identification of C4-spirocyclopropane 5 (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 2 is proposed.

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