| 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 PubMed
Identification of orthosteric mGlu2/3 receptor agonists capable of discriminating between individual mGlu2 and mGlu3 subtypes has been highly challenging owing to the glutamate-site sequence homology between these proteins. Herein we detail the preparation and characterization of a series of molecules related to 1S,2S,5R,6S-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate 1 (LY354740) bearing C4-thiotriazole substituents. Based on second messenger responses in cells expressing recombinant human mGlu2/3 subtypes, a number of high potency and efficacy mGlu2 receptor agonists exhibiting low potency mGlu3 partial agonist / antagonist activity were identified. From this, (1R,2S,4R,5R,6R)-2-Amino-4-(1H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2, 6-dicarboxylic acid 14a (LY2812223) was further characterized. Co-crystallization of 14a with the amino terminal domains of hmGlu2 and hmGlu3 combined with site-directed mutation studies has clarified the underlying molecular basis of this unique pharmacology. Evaluation of 14a in a rat model responsive to mGlu2 receptor activation coupled with a measure of central drug disposition provides evidence that this molecule engages and activates central mGlu2 receptors in vivo.
Synthesis and Pharmacological Characterization of C4-(Thiotriazolyl)-Substituted-2-Aminobicyclo[3.1.0]hexane-2,6-Dicarboxylates. Identification of (1R,2S,4R,5R,6R)-2-Amino-4-(1H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2, 6-dicarboxylic acid (LY2812223), a Highly Potent, Functionally Selective mGlu2 Receptor Agonist.,Monn JA, Prieto L, Taboada L, Hao J, Reinhard MR, Henry SS, Beadle CD, Walton L, Man T, Rudyk H, Clark B, Tupper D, Baker SR, Lamas C, Montero C, Marcos A, Blanco J, Bures M, Clawson DK, Atwell S, Lu F, Wang J, Russell M, Heinz BA, Wang X, Carter JH, Getman BG, Catlow JT, Swanson S, Johnson BG, Shaw DB, McKinzie DL J Med Chem. 2015 Aug 27. PMID:26313429[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Gonzalez-Maeso J, Ang RL, Yuen T, Chan P, Weisstaub NV, Lopez-Gimenez JF, Zhou M, Okawa Y, Callado LF, Milligan G, Gingrich JA, Filizola M, Meana JJ, Sealfon SC. Identification of a serotonin/glutamate receptor complex implicated in psychosis. Nature. 2008 Mar 6;452(7183):93-7. doi: 10.1038/nature06612. Epub 2008 Feb 24. PMID:18297054 doi:http://dx.doi.org/10.1038/nature06612
- ↑ Delille HK, Becker JM, Burkhardt S, Bleher B, Terstappen GC, Schmidt M, Meyer AH, Unger L, Marek GJ, Mezler M. Heterocomplex formation of 5-HT2A-mGlu2 and its relevance for cellular signaling cascades. Neuropharmacology. 2012 Jun;62(7):2184-91. doi: 10.1016/j.neuropharm.2012.01.010., Epub 2012 Jan 25. PMID:22300836 doi:http://dx.doi.org/10.1016/j.neuropharm.2012.01.010
- ↑ Moreno JL, Muguruza C, Umali A, Mortillo S, Holloway T, Pilar-Cuellar F, Mocci G, Seto J, Callado LF, Neve RL, Milligan G, Sealfon SC, Lopez-Gimenez JF, Meana JJ, Benson DL, Gonzalez-Maeso J. Identification of three residues essential for 5-hydroxytryptamine 2A-metabotropic glutamate 2 (5-HT2A.mGlu2) receptor heteromerization and its psychoactive behavioral function. J Biol Chem. 2012 Dec 28;287(53):44301-19. doi: 10.1074/jbc.M112.413161. Epub, 2012 Nov 5. PMID:23129762 doi:http://dx.doi.org/10.1074/jbc.M112.413161
- ↑ Flor PJ, Lindauer K, Puttner I, Ruegg D, Lukic S, Knopfel T, Kuhn R. Molecular cloning, functional expression and pharmacological characterization of the human metabotropic glutamate receptor type 2. Eur J Neurosci. 1995 Apr 1;7(4):622-9. PMID:7620613
- ↑ Monn JA, Prieto L, Taboada L, Hao J, Reinhard MR, Henry SS, Beadle CD, Walton L, Man T, Rudyk H, Clark B, Tupper D, Baker SR, Lamas C, Montero C, Marcos A, Blanco J, Bures M, Clawson DK, Atwell S, Lu F, Wang J, Russell M, Heinz BA, Wang X, Carter JH, Getman BG, Catlow JT, Swanson S, Johnson BG, Shaw DB, McKinzie DL. Synthesis and Pharmacological Characterization of C4-(Thiotriazolyl)-Substituted-2-Aminobicyclo[3.1.0]hexane-2,6-Dicarboxylates. Identification of (1R,2S,4R,5R,6R)-2-Amino-4-(1H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2, 6-dicarboxylic acid (LY2812223), a Highly Potent, Functionally Selective mGlu2 Receptor Agonist. J Med Chem. 2015 Aug 27. PMID:26313429 doi:http://dx.doi.org/10.1021/acs.jmedchem.5b01124
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