Synthesis and Pharmacological Characterization of C4β-Amide-Substituted 2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylates. Identification of (1S,2S,4S,5R,6S)-2-Amino-4-[(3-methoxybenzoyl)amino]bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid (LY2794193), a Highly Potent and Selective mGlu3 Receptor Agonist
| Autor: | Frances Lu, Bryan G. Johnson, Daniel Ursu, Joan H. Carter, Lisa M. Broad, Kofi Adragni, Shane Atwell, Jing Wang, David K. Clawson, Beverly A. Heinz, Steven P. Swanson, James A. Monn, Qi Chen, Helene E. Sanger, David B. Shaw, Steven Marc Massey, Xushan Wang, Marijane Russell, Steven S. Henry, Junliang Hao, Rajni M. Bhardwaj, Diseroad Benjamin Alan, David L. McKinzie, Brian G. Getman, John T. Catlow |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
chemistry.chemical_classification Agonist Bicyclic molecule Stereochemistry medicine.drug_class Glutamate binding Ligand (biochemistry) Small molecule 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Metabotropic receptor Dicarboxylic acid chemistry Drug Discovery medicine Molecular Medicine Receptor 030217 neurology & neurosurgery |
| Zdroj: | Journal of Medicinal Chemistry. 61:2303-2328 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.7b01481 |
| Popis: | Multiple therapeutic opportunities have been suggested for compounds capable of selective activation of metabotropic glutamate 3 (mGlu3) receptors, but small molecule tools are lacking. As part of our ongoing efforts to identify potent, selective, and systemically bioavailable agonists for mGlu2 and mGlu3 receptor subtypes, a series of C4β-N-linked variants of (1S,2S,5R,6S)-2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 1 (LY354740) were prepared and evaluated for both mGlu2 and mGlu3 receptor binding affinity and functional cellular responses. From this investigation we identified (1S,2S,4S,5R,6S)-2-amino-4-[(3-methoxybenzoyl)amino]bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 8p (LY2794193), a molecule that demonstrates remarkable mGlu3 receptor selectivity. Crystallization of 8p with the amino terminal domain of hmGlu3 revealed critical binding interactions for this ligand with residues adjacent to the glutamate binding site, while pharmacokinetic assessment of 8p combined with its effect in an mGlu2 ... |
| Databáze: | OpenAIRE |
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