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

• Published in: Journal of medicinal chemistry Vol. 58; no. 4; pp. 1776 - 1794
• Main Authors: Monn, James A, Prieto, Lourdes, Taboada, Lorena, Pedregal, Concepcion, Hao, Junliang, Reinhard, Matt R, Henry, Steven S, Goldsmith, Paul J, Beadle, Christopher D, Walton, Lesley, Man, Teresa, Rudyk, Helene, Clark, Barry, Tupper, David, Baker, S. Richard, Lamas, Carlos, Montero, Carlos, Marcos, Alicia, Blanco, Jaime, Bures, Mark, Clawson, David K, Atwell, Shane, Lu, Frances, Wang, Jing, Russell, Marijane, Heinz, Beverly A, Wang, Xushan, Carter, Joan H, Xiang, Chuanxi, Catlow, John T, Swanson, Steven, Sanger, Helen, Broad, Lisa M, Johnson, Michael P, Knopp, Kelly L, Simmons, Rosa M. A, Johnson, Bryan G, Shaw, David B, McKinzie, David L
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 26.02.2015; Amer Chemical Soc
• Subjects: Animals; Bridged Bicyclo Compounds - chemistry; Bridged Bicyclo Compounds - metabolism; Bridged Bicyclo Compounds - pharmacology; Chemistry, Medicinal; Crystallography, X-Ray; Humans; Life Sciences & Biomedicine; Male; Models, Molecular; Pharmacology & Pharmacy; Protein Structure, Tertiary; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate - agonists; Receptors, Metabotropic Glutamate - chemistry; Receptors, Metabotropic Glutamate - genetics; Science & Technology; Spiro Compounds - chemistry; Spiro Compounds - metabolism; Spiro Compounds - pharmacology; DRUG; CELLS; KNOCK-OUT MICE; ACTIVATION; MOOD DISORDERS; ANXIETY; POSITIVE ALLOSTERIC MODULATORS; ACID LY354740; SCHIZOPHRENIA; NEUROPROTECTION
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm501612y

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.