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 PMID: 25602126

ADC Targets in Oncology

2026-04-10

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

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.