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== Function == | == Function == | ||
[[http://www.uniprot.org/uniprot/GRM2_HUMAN GRM2_HUMAN]] G-protein coupled receptor for glutamate. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling inhibits adenylate cyclase activity. May mediate suppression of neurotransmission or may be involved in synaptogenesis or synaptic stabilization.<ref>PMID:18297054</ref> <ref>PMID:22300836</ref> <ref>PMID:23129762</ref> <ref>PMID:7620613</ref> | [[http://www.uniprot.org/uniprot/GRM2_HUMAN GRM2_HUMAN]] G-protein coupled receptor for glutamate. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling inhibits adenylate cyclase activity. May mediate suppression of neurotransmission or may be involved in synaptogenesis or synaptic stabilization.<ref>PMID:18297054</ref> <ref>PMID:22300836</ref> <ref>PMID:23129762</ref> <ref>PMID:7620613</ref> | ||
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== Publication Abstract from PubMed == | |||
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-bicy clo[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. | |||
Discovery of (1S,2R,3S,4S,5R,6R)-2-Amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicy clo[3.1.0]hexane-2,6-dicarboxylic Acid Hydrochloride (LY3020371.HCl): A Potent, Metabotropic Glutamate 2/3 Receptor Antagonist with Antidepressant-Like Activity.,Chappell MD, Li R, Smith SC, Dressman BA, Tromiczak EG, Tripp AE, Blanco MJ, Vetman T, Quimby SJ, Matt J, Britton TC, Fivush AM, Schkeryantz JM, Mayhugh D, Erickson JA, Bures MG, Jaramillo C, Carpintero M, Diego JE, Barberis M, Garcia-Cerrada S, Soriano JF, Antonysamy S, Atwell S, MacEwan I, Condon B, Sougias C, Wang J, Zhang A, Conners K, Groshong C, Wasserman SR, Koss JW, Witkin JM, Li X, Overshiner C, Wafford KA, Seidel W, Wang XS, Heinz BA, Swanson S, Catlow JT, Bedwell DW, Monn JA, Mitch CH, Ornstein PL J Med Chem. 2016 Dec 22;59(24):10974-10993. Epub 2016 Dec 6. PMID:28002967<ref>PMID:28002967</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
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== References == | == References == | ||
<references/> | <references/> | ||
Revision as of 12:39, 4 January 2017
Metabotropic Glutamate ReceptorMetabotropic Glutamate Receptor
Structural highlights
Function[GRM2_HUMAN] G-protein coupled receptor for glutamate. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling inhibits adenylate cyclase activity. May mediate suppression of neurotransmission or may be involved in synaptogenesis or synaptic stabilization.[1] [2] [3] [4] Publication Abstract from PubMedAs 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-bicy clo[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. Discovery of (1S,2R,3S,4S,5R,6R)-2-Amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicy clo[3.1.0]hexane-2,6-dicarboxylic Acid Hydrochloride (LY3020371.HCl): A Potent, Metabotropic Glutamate 2/3 Receptor Antagonist with Antidepressant-Like Activity.,Chappell MD, Li R, Smith SC, Dressman BA, Tromiczak EG, Tripp AE, Blanco MJ, Vetman T, Quimby SJ, Matt J, Britton TC, Fivush AM, Schkeryantz JM, Mayhugh D, Erickson JA, Bures MG, Jaramillo C, Carpintero M, Diego JE, Barberis M, Garcia-Cerrada S, Soriano JF, Antonysamy S, Atwell S, MacEwan I, Condon B, Sougias C, Wang J, Zhang A, Conners K, Groshong C, Wasserman SR, Koss JW, Witkin JM, Li X, Overshiner C, Wafford KA, Seidel W, Wang XS, Heinz BA, Swanson S, Catlow JT, Bedwell DW, Monn JA, Mitch CH, Ornstein PL J Med Chem. 2016 Dec 22;59(24):10974-10993. Epub 2016 Dec 6. PMID:28002967[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)
OCA- Antonysamy, S
- Atwell, S
- Barberis, M
- Bedwell, D
- Blanco, M J
- Bradley, C
- Britton, T
- Bures, M
- Carpintero, M
- Catlow, J
- Chappell, M D
- Condon, B
- Conners, K
- Diego, J E.de
- Dressman, B A
- Erickson, J A
- Fivush, A M
- Garcia-Cerrada, S
- Groshong, C
- Heinz, B A
- Jaramillo, C
- Koss, J W
- Li, R
- Li, X
- MacEwan, I
- Matt, J
- Mayhugh, D
- Mitch, C H
- Monn, J A
- Ornstein, P
- Overshiner, C
- Quimby, S J
- Schkeryantz, J M
- Seidel, W
- Smith, S C
- Soriano, J F
- Swanson, S
- Tripp, A E
- Tromiczak, E G
- Vetman, T
- Wafford, K A
- Wang, J
- Wang, X S
- Wasserman, S R
- Witkin, J M
- Zhang, A
- Antagonist
- Antidepressent
- Mglur2
- Signaling protein