1377615-91-2Relevant academic research and scientific papers
Discovery of (1S,2R,3S,4S,5R,6R)-2-Amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid Hydrochloride (LY3020371·HCl): A Potent, Metabotropic Glutamate 2/3 Receptor Antagonist with Antidepressant-Like Activity
Chappell, Mark D.,Li, Renhua,Smith, Stephon C.,Dressman, Bruce A.,Tromiczak, Eric G.,Tripp, Allie E.,Blanco, Maria-Jesus,Vetman, Tatiana,Quimby, Steven J.,Matt, James,Britton, Thomas C.,Fivush, Adam M.,Schkeryantz, Jeffrey M.,Mayhugh, Daniel,Erickson, Jon A.,Bures, Mark G.,Jaramillo, Carlos,Carpintero, Mercedes,Diego, José Eugenio De,Barberis, Mario,Garcia-Cerrada, Susana,Soriano, José F.,Antonysamy, Stephen,Atwell, Shane,Macewan, Iain,Condon, Bradley,Sougias, Christine,Wang, Jing,Zhang, Aiping,Conners, Kris,Groshong, Chris,Wasserman, Stephen R.,Koss, John W.,Witkin, Jeffrey M.,Li, Xia,Overshiner, Carl,Wafford, Keith A.,Seidel, Wesley,Wang, Xu-Shan,Heinz, Beverly A.,Swanson, Steven,Catlow, John T.,Bedwell, David W.,Monn, James A.,Mitch, Charles H.,Ornstein, Paul L.
, p. 10974 - 10993 (2016/12/30)
As part of our ongoing efforts to identify novel ligands for the metabotropic glutamate 2 and 3 (mGlu2/3) receptors, we have incorporated substitution at the C3 and C4 positions of the (1S,2R,5R,6R)-2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid scaffold to generate mGlu2/3 antagonists. Exploration of this structure-activity relationship (SAR) led to the identification of (1S,2R,3S,4S,5R,6R)-2-amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid hydrochloride (LY3020371·HCl, 19f), a potent, selective, and maximally efficacious mGlu2/3 antagonist. Further characterization of compound 19f binding to the human metabotropic 2 glutamate (hmGlu2) site was established by cocrystallization of this molecule with the amino terminal domain (ATD) of the hmGlu2 receptor protein. The resulting cocrystal structure revealed the specific ligand-protein interactions, which likely explain the high affinity of 19f for this site and support its functional mGlu2 antagonist pharmacology. Further characterization of 19f in vivo demonstrated an antidepressant-like signature in the mouse forced-swim test (mFST) assay when brain levels of this compound exceeded the cellular mGlu2 IC50 value.
4-SUBSTITUTED-3-PHENYLSULFANYLMETHYL-BICYCLO[3.1.0]HEXANE COMPOUNDS AS mGluR 2/3 ANTAGONISTS
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, (2012/06/01)
A mGlu2/3 receptor antagonist of the formula: its uses, and methods for its preparation are described.
