
Journal of Medicinal Chemistry p. 10974 - 10993 (2016)
Update date:2022-08-15
Topics:
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.
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.
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