Insights into the Structural Aspects of the mGlu Receptor Orthosteric Binding Site

Author(s): Junliang Hao*, Qi Chen

Journal Name: Current Topics in Medicinal Chemistry

Volume 19 , Issue 26 , 2019

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Graphical Abstract:


The amino terminal domain (ATD) of the metabotropic glutamate (mGlu) receptors contains the orthosteric glutamate recognition site, which is highly conserved across the eight mGlu receptor subtypes. In total, 29 X-ray crystal structures of the mGlu ATD proteins have been reported to date. These structures span across 3 subgroups and 6 subtypes, and include apo, agonist- and antagonist-bound structures. We will discuss the insights gained from the analysis of these structures with the focus on the interactions contributing to the observed group and subtype selectivity for select agonists. Furthermore, we will define the full expanded orthosteric ligand binding pocket (LBP) of the mGlu receptors, and discuss the macroscopic features of the mGlu ATD proteins.

Keywords: Class C GPCR, mGlu Receptor, Orthosteric ligand binding pocket, Structure-based drug design, Receptor activation, L-Glutamate.

Kew, J.N.; Kemp, J.A. Ionotropic and metabotropic glutamate receptor structure and pharmacology. Psychopharmacology (Berl.), 2005, 179(1), 4-29.
[] [PMID: 15731895]
Traynelis, S.F.; Wollmuth, L.P.; McBain, C.J.; Menniti, F.S.; Vance, K.M.; Ogden, K.K.; Hansen, K.B.; Yuan, H.; Myers, S.J.; Dingledine, R. Glutamate receptor ion channels: structure, regulation, and function. Pharmacol. Rev., 2010, 62(3), 405-496.
[] [PMID: 20716669]
Golubeva, A.V.; Moloney, R.D.; O’Connor, R.M.; Dinan, T.G.; Cryan, J.F. Metabotropic glutamate receptors in central nervous system diseases. Curr. Drug Targets, 2016, 17(5), 538-616.
[] [PMID: 25777273]
Ribeiro, F.M.; Vieira, L.B.; Pires, R.G.; Olmo, R.P.; Ferguson, S.S. Metabotropic glutamate receptors and neurodegenerative diseases. Pharmacol. Res., 2017, 115, 179-191.
[] [PMID: 27872019]
Hao, J.; Chen, Q. On the origin of the 2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate scaffold’s unique group II selectivity for the mGlu receptors. Bioorg. Med. Chem. Lett., 2019, 29(2), 297-301.
[] [PMID: 30470494]
Kunishima, N.; Shimada, Y.; Tsuji, Y.; Sato, T.; Yamamoto, M.; Kumasaka, T.; Nakanishi, S.; Jingami, H.; Morikawa, K. Structural basis of glutamate recognition by a dimeric metabotropic glutamate receptor. Nature, 2000, 407(6807), 971-977.
[] [PMID: 11069170]
Chappell, M.D.; Li, R.; Smith, S.C.; Dressman, B.A.; Tromiczak, E.G.; Tripp, A.E.; Blanco, M-J.; Vetman, T.; Quimby, S.J.; Matt, J.; Britton, T.C.; Fivush, A.M.; Schkeryantz, J.M.; Mayhugh, D.; Erickson, J.A.; Bures, M.G.; Jaramillo, C.; Carpintero, M.; Diego, J.E.; Barberis, M.; Garcia-Cerrada, S.; Soriano, J.F.; Antonysamy, S.; Atwell, S.; MacEwan, I.; Condon, B.; Sougias, C.; Wang, J.; Zhang, A.; Conners, K.; Groshong, C.; Wasserman, S.R.; Koss, J.W.; Witkin, J.M.; Li, X.; Overshiner, C.; Wafford, K.A.; Seidel, W.; Wang, X-S.; Heinz, B.A.; Swanson, S.; Catlow, J.T.; Bedwell, D.W.; Monn, J.A.; Mitch, C.H.; Ornstein, P.L. 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. J. Med. Chem., 2016, 59(24), 10974-10993.
[] [PMID: 28002967]
Kingston, A.E.; Ornstein, P.L.; Wright, R.A.; Johnson, B.G.; Mayne, N.G.; Burnett, J.P.; Belagaje, R.; Wu, S.; Schoepp, D.D. LY341495 is a nanomolar potent and selective antagonist of group II metabotropic glutamate receptors. Neuropharmacology, 1998, 37(1), 1-12.
[] [PMID: 9680254]
Monn, J.A.; Massey, S.M.; Valli, M.J.; Henry, S.S.; Stephenson, G.A.; Bures, M.; Hérin, M.; Catlow, J.; Giera, D.; Wright, R.A.; Johnson, B.G.; Andis, S.L.; Kingston, A.; Schoepp, D.D. Synthesis and metabotropic glutamate receptor activity of S-oxidized variants of (-)-4-amino-2-thiabicyclo-[3.1.0]hexane-4,6-dicarboxylate: identification of potent, selective, and orally bioavailable agonists for mGlu2/3 receptors. J. Med. Chem., 2007, 50(2), 233-240.
[] [PMID: 17228865]
Monn, J.A.; Prieto, L.; Taboada, L.; Pedregal, C.; Hao, J.; Reinhard, M.R.; Henry, S.S.; Goldsmith, P.J.; Beadle, C.D.; Walton, L.; Man, T.; Rudyk, H.; Clark, B.; Tupper, D.; Baker, S.R.; Lamas, C.; Montero, C.; Marcos, A.; Blanco, J.; Bures, M.; Clawson, D.K.; Atwell, S.; Lu, F.; Wang, J.; Russell, M.; Heinz, B.A.; Wang, X.; Carter, J.H.; Xiang, C.; Catlow, J.T.; Swanson, S.; Sanger, H.; Broad, L.M.; Johnson, M.P.; Knopp, K.L.; Simmons, R.M.; Johnson, B.G.; Shaw, D.B.; McKinzie, D.L. 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. J. Med. Chem., 2015, 58(4), 1776-1794.
[] [PMID: 25602126]
Monn, J.A.; Valli, M.J.; Massey, S.M.; Hansen, M.M.; Kress, T.J.; Wepsiec, J.P.; Harkness, A.R.; Grutsch, J.L., Jr; Wright, R.A.; Johnson, B.G.; Andis, S.L.; Kingston, A.; Tomlinson, R.; Lewis, R.; Griffey, K.R.; Tizzano, J.P.; Schoepp, D.D. Synthesis, pharmacological characterization, and molecular modeling of heterobicyclic amino acids related to (+)-2-aminobicyclo[3.1.0] hexane-2,6-dicarboxylic acid (LY354740): identification of two new potent, selective, and systemically active agonists for group II metabotropic glutamate receptors. J. Med. Chem., 1999, 42(6), 1027-1040.
[] [PMID: 10090786]
Monn, J.A.; Valli, M.J.; Massey, S.M.; Hao, J.; Reinhard, M.R.; Bures, M.G.; Heinz, B.A.; Wang, X.; Carter, J.H.; Getman, B.G.; Stephenson, G.A.; Herin, M.; Catlow, J.T.; Swanson, S.; Johnson, B.G.; McKinzie, D.L.; Henry, S.S. Synthesis and pharmacological characterization of 4-substituted-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylates: identification of new potent and selective metabotropic glutamate 2/3 receptor agonists. J. Med. Chem., 2013, 56(11), 4442-4455.
[] [PMID: 23675965]
Monn, J.A.; Valli, M.J.; Massey, S.M.; Wright, R.A.; Salhoff, C.R.; Johnson, B.G.; Howe, T.; Alt, C.A.; Rhodes, G.A.; Robey, R.L.; Griffey, K.R.; Tizzano, J.P.; Kallman, M.J.; Helton, D.R.; Schoepp, D.D. Design, synthesis, and pharmacological characterization of (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740): a potent, selective, and orally active group 2 metabotropic glutamate receptor agonist possessing anticonvulsant and anxiolytic properties. J. Med. Chem., 1997, 40(4), 528-537.
[] [PMID: 9046344]
Chaki, S.; Yoshikawa, R.; Hirota, S.; Shimazaki, T.; Maeda, M.; Kawashima, N.; Yoshimizu, T.; Yasuhara, A.; Sakagami, K.; Okuyama, S.; Nakanishi, S.; Nakazato, A. MGS0039: a potent and selective group II metabotropic glutamate receptor antagonist with antidepressant-like activity. Neuropharmacology, 2004, 46(4), 457-467.
[] [PMID: 14975669]
Nakazato, A.; Kumagai, T.; Sakagami, K.; Yoshikawa, R.; Suzuki, Y.; Chaki, S.; Ito, H.; Taguchi, T.; Nakanishi, S.; Okuyama, S. Synthesis, SARs, and pharmacological characterization of 2-amino-3 or 6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives as potent, selective, and orally active group II metabotropic glutamate receptor agonists. J. Med. Chem., 2000, 43(25), 4893-4909.
[] [PMID: 11123999]
Nakazato, A.; Sakagami, K.; Yasuhara, A.; Ohta, H.; Yoshikawa, R.; Itoh, M.; Nakamura, M.; Chaki, S. Synthesis, in vitro pharmacology, structure-activity relationships, and pharmacokinetics of 3-alkoxy-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives as potent and selective group II metabotropic glutamate receptor antagonists. J. Med. Chem., 2004, 47(18), 4570-4587.
[] [PMID: 15317467]
Thomsen, C. The L-AP4 receptor. Gen. Pharmacol., 1997, 29(2), 151-158.
[] [PMID: 9251893]
Thomas, N.K.; Wright, R.A.; Howson, P.A.; Kingston, A.E.; Schoepp, D.D.; Jane, D.E. (S)-3,4-DCPG, a potent and selective mGlu8a receptor agonist, activates metabotropic glutamate receptors on primary afferent terminals in the neonatal rat spinal cord. Neuropharmacology, 2001, 40(3), 311-318.
[] [PMID: 11166323]
Monn, J.A.; Prieto, L.; Taboada, L.; Hao, J.; Reinhard, M.R.; Henry, S.S.; Beadle, C.D.; Walton, L.; Man, T.; Rudyk, H.; Clark, B.; Tupper, D.; Baker, S.R.; Lamas, C.; Montero, C.; Marcos, A.; Blanco, J.; Bures, M.; Clawson, D.K.; Atwell, S.; Lu, F.; Wang, J.; Russell, M.; Heinz, B.A.; Wang, X.; Carter, J.H.; Getman, B.G.; Catlow, J.T.; Swanson, S.; Johnson, B.G.; Shaw, D.B.; McKinzie, D.L. 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, 58(18), 7526-7548.
[] [PMID: 26313429]
Monn, J.A.; Henry, S.S.; Massey, S.M.; Clawson, D.K.; Chen, Q.; Diseroad, B.A.; Bhardwaj, R.M.; Atwell, S.; Lu, F.; Wang, J.; Russell, M.; Heinz, B.A.; Wang, X-S.; Carter, J.H.; Getman, B.G.; Adragni, K.; Broad, L.M.; Sanger, H.E.; Ursu, D.; Catlow, J.T.; Swanson, S.; Johnson, B.G.; Shaw, D.B.; McKinzie, D.L.; Hao, J. Synthesis and pharmacological characterization of C4beta-amide-substituted 2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylates: Identification of (1 S,2 S,4 S,5 R,6 S)-2-amino-4-[(3-methoxybenzoyl)amino]bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY2794193), a highly potent and selective mGlu3 receptor agonist. J. Med. Chem., 2018, 61(6), 2303-2328.
[] [PMID: 29350927]
Patil, S.T.; Zhang, L.; Martenyi, F.; Lowe, S.L.; Jackson, K.A.; Andreev, B.V.; Avedisova, A.S.; Bardenstein, L.M.; Gurovich, I.Y.; Morozova, M.A.; Mosolov, S.N.; Neznanov, N.G.; Reznik, A.M.; Smulevich, A.B.; Tochilov, V.A.; Johnson, B.G.; Monn, J.A.; Schoepp, D.D. Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial. Nat. Med., 2007, 13(9), 1102-1107.
[] [PMID: 17767166]
Adams, D.H.; Kinon, B.J.; Baygani, S.; Millen, B.A.; Velona, I.; Kollack-Walker, S.; Walling, D.P. A long-term, phase 2, multicenter, randomized, open-label, comparative safety study of pomaglumetad methionil (LY2140023 monohydrate) versus atypical antipsychotic standard of care in patients with schizophrenia. BMC Psychiatry, 2013, 13, 143.
[] [PMID: 23694720]
Adams, D.H.; Zhang, L.; Millen, B.A.; Kinon, B.J.; Gomez, J.C. Pomaglumetad methionil (LY2140023 Monohydrate) and aripiprazole in patients with schizophrenia: A phase 3, multicenter, double-blind comparison. Schizophr. Res. Treatment, 2014.2014758212
[] [PMID: 24772351]
Downing, A.M.; Kinon, B.J.; Millen, B.A.; Zhang, L.; Liu, L.; Morozova, M.A.; Brenner, R.; Rayle, T.J.; Nisenbaum, L.; Zhao, F.; Gomez, J.C.A. double-blind, placebo-controlled comparator study of LY2140023 monohydrate in patients with schizophrenia. BMC Psychiatry, 2014, 14, 351.
[] [PMID: 25539791]
Kinon, B.J.; Zhang, L.; Millen, B.A.; Osuntokun, O.O.; Williams, J.E.; Kollack-Walker, S.; Jackson, K.; Kryzhanovskaya, L.; Jarkova, N.; Group, H.S. A multicenter, inpatient, phase 2, double-blind, placebo-controlled dose-ranging study of LY2140023 monohydrate in patients with DSM-IV schizophrenia. J. Clin. Psychopharmacol., 2011, 31(3), 349-355.
[] [PMID: 21508856]
Bergink, V.; Westenberg, H.G. Metabotropic glutamate II receptor agonists in panic disorder: a double blind clinical trial with LY354740. Int. Clin. Psychopharmacol., 2005, 20(6), 291-293.
[] [PMID: 16192835]
Bueno, A.B.; Collado, I.; de Dios, A.; Domínguez, C.; Martín, J.A.; Martín, L.M.; Martínez-Grau, M.A.; Montero, C.; Pedregal, C.; Catlow, J.; Coffey, D.S.; Clay, M.P.; Dantzig, A.H.; Lindstrom, T.; Monn, J.A.; Jiang, H.; Schoepp, D.D.; Stratford, R.E.; Tabas, L.B.; Tizzano, J.P.; Wright, R.A.; Herin, M.F. Dipeptides as effective prodrugs of the unnatural amino acid (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740), a selective group II metabotropic glutamate receptor agonist. J. Med. Chem., 2005, 48(16), 5305-5320.
[] [PMID: 16078848]
Mezler, M.; Geneste, H.; Gault, L.; Marek, G.J. LY-2140023, a prodrug of the group II metabotropic glutamate receptor agonist LY-404039 for the potential treatment of schizophrenia. Curr. Opin. Investig. Drugs, 2010, 11(7), 833-845.
[PMID: 20571979]
Nakamura, M.; Kawakita, Y.; Yasuhara, A.; Fukasawa, Y.; Yoshida, K.; Sakagami, K.; Nakazato, A. In vitro and in vivo evaluation of the metabolism and bioavailability of ester prodrugs of mgs0039 (3-(3,4-dichlorobenzyloxy)-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic Acid), a potent metabotropic glutamate receptor antagonist. Drug Metab. Dispos., 2006, 34(3), 369-374.
[] [PMID: 16326817]
Perkins, E.J.; Abraham, T. Pharmacokinetics, metabolism, and excretion of the intestinal peptide transporter 1 (SLC15A1)-targeted prodrug (1S,2S,5R,6S)-2-[(2'S)-(2-amino)propionyl]aminobicyclo[3.1.0.]hexen-2,6-dicarboxylic acid (LY544344) in rats and dogs: assessment of first-pass bioactivation and dose linearity. Drug Metab. Dispos., 2007, 35(10), 1903-1909.
[] [PMID: 17646281]
Rorick-Kehn, L.M.; Perkins, E.J.; Knitowski, K.M.; Hart, J.C.; Johnson, B.G.; Schoepp, D.D.; McKinzie, D.L. Improved bioavailability of the mGlu2/3 receptor agonist LY354740 using a prodrug strategy: in vivo pharmacology of LY544344. J. Pharmacol. Exp. Ther., 2006, 316(2), 905-913.
[] [PMID: 16223873]
Yasuhara, A.; Nakamura, M.; Sakagami, K.; Shimazaki, T.; Yoshikawa, R.; Chaki, S.; Ohta, H.; Nakazato, A. Prodrugs of 3-(3,4-dichlorobenzyloxy)-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (MGS0039): a potent and orally active group II mGluR antagonist with antidepressant-like potential. Bioorg. Med. Chem., 2006, 14(12), 4193-4207.
[] [PMID: 16487713]
Doré, A.S.; Okrasa, K.; Patel, J.C.; Serrano-Vega, M.; Bennett, K.; Cooke, R.M.; Errey, J.C.; Jazayeri, A.; Khan, S.; Tehan, B.; Weir, M.; Wiggin, G.R.; Marshall, F.H. Structure of class C GPCR metabotropic glutamate receptor 5 transmembrane domain. Nature, 2014, 511(7511), 557-562.
[] [PMID: 25042998]
Wu, H.; Wang, C.; Gregory, K.J.; Han, G.W.; Cho, H.P.; Xia, Y.; Niswender, C.M.; Katritch, V.; Meiler, J.; Cherezov, V.; Conn, P.J.; Stevens, R.C. Structure of a class C GPCR metabotropic glutamate receptor 1 bound to an allosteric modulator. Science, 2014, 344(6179), 58-64.
[] [PMID: 24603153]
Christopher, J.A.; Aves, S.J.; Bennett, K.A.; Doré, A.S.; Errey, J.C.; Jazayeri, A.; Marshall, F.H.; Okrasa, K.; Serrano-Vega, M.J.; Tehan, B.G.; Wiggin, G.R.; Congreve, M. Fragment and structure-based drug discovery for a class C GPCR: discovery of the MGLU5 negative allosteric modulator HTL14242 (3-Chloro-5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzonitrile). J. Med. Chem., 2015, 58(16), 6653-6664.
[] [PMID: 26225459]
Changeux, J.P.; Christopoulos, A. Allosteric modulation as a unifying mechanism for receptor function and regulation. Cell, 2016, 166(5), 1084-1102.
[] [PMID: 27565340]
May, L.T.; Leach, K.; Sexton, P.M.; Christopoulos, A. Allosteric modulation of G protein-coupled receptors. Annu. Rev. Pharmacol. Toxicol., 2007, 47, 1-51.
[] [PMID: 17009927]
Annoura, H.; Fukunaga, A.; Uesugi, M.; Tatsuoka, T.; Horikawa, Y. A novel class of antagonists for metabotropic glutamate receptors, 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylates. Bioorg. Med. Chem. Lett., 1996, 6, 763-766.
O’Brien, D.E.; Shaw, D.M.; Cho, H.P.; Cross, A.J.; Wesolowski, S.S.; Felts, A.S.; Bergare, J.; Elmore, C.S.; Lindsley, C.W.; Niswender, C.M.; Conn, P.J. Differential pharmacology and binding of mGlu2 receptor allosteric modulators. Mol. Pharmacol., 2018, 93(5), 526-540.
[] [PMID: 29545267]
Engers, J.L.; Rodriguez, A.L.; Konkol, L.C.; Morrison, R.D.; Thompson, A.D.; Byers, F.W.; Blobaum, A.L.; Chang, S.; Venable, D.F.; Loch, M.T.; Niswender, C.M.; Daniels, J.S.; Jones, C.K.; Conn, P.J.; Lindsley, C.W.; Emmitte, K.A. Discovery of a selective and CNS penetrant negative allosteric modulator of metabotropic glutamate receptor subtype 3 with antidepressant and anxiolytic activity in rodents. J. Med. Chem., 2015, 58(18), 7485-7500.
[] [PMID: 26335039]
Engers, D.W.; Blobaum, A.L.; Gogliotti, R.D.; Cheung, Y.Y.; Salovich, J.M.; Garcia-Barrantes, P.M.; Daniels, J.S.; Morrison, R.; Jones, C.K.; Soars, M.G.; Zhuo, X.; Hurley, J.; Macor, J.E.; Bronson, J.J.; Conn, P.J.; Lindsley, C.W.; Niswender, C.M.; Hopkins, C.R. Discovery, synthesis, and preclinical characterization of N-(3-chloro-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-3-amine (VU0418506), a novel positive allosteric modulator of the metabotropic glutamate receptor 4 (mGlu4). ACS Chem. Neurosci., 2016, 7(9), 1192-1200.
[] [PMID: 27075300]
Gogliotti, R.D.; Blobaum, A.L.; Morrison, R.M.; Daniels, J.S.; Salovich, J.M.; Cheung, Y.Y.; Rodriguez, A.L.; Loch, M.T.; Conn, P.J.; Lindsley, C.W.; Niswender, C.M.; Hopkins, C.R. Discovery and characterization of a novel series of N-phenylsulfonyl-1H-pyrrole picolinamides as positive allosteric modulators of the metabotropic glutamate receptor 4 (mGlu4). Bioorg. Med. Chem. Lett., 2016, 26(13), 2984-2987.
[] [PMID: 27234146]
Niswender, C.M.; Jones, C.K.; Lin, X.; Bubser, M.; Thompson Gray, A.; Blobaum, A.L.; Engers, D.W.; Rodriguez, A.L.; Loch, M.T.; Daniels, J.S.; Lindsley, C.W.; Hopkins, C.R.; Javitch, J.A.; Conn, P.J. Development and antiparkinsonian activity of VU0418506, a selective positive allosteric modulator of metabotropic glutamate receptor 4 homomers without activity at mGlu2/4 heteromers. ACS Chem. Neurosci., 2016, 7(9), 1201-1211.
[] [PMID: 27441572]
Ponnazhagan, R.; Harms, A.S.; Thome, A.D.; Jurkuvenaite, A.; Gogliotti, R.; Niswender, C.M.; Conn, P.J.; Standaert, D.G. The metabotropic glutamate receptor 4 positive allosteric modulator ADX88178 inhibits inflammatory responses in primary microglia. J. Neuroimmune Pharmacol., 2016, 11(2), 231-237.
[] [PMID: 26872456]
Emmitte, K.A. mGlu5 negative allosteric modulators: a patent review (2013-2016). Expert Opin. Ther. Pat., 2017, 27, 691-706.
Hao, J.; Xiong, H. SAR studies on mGlu5 receptor positive allosteric modulators (2003-2013). Curr. Top. Med. Chem., 2014, 14(15), 1789-1841.
[] [PMID: 25176124]
Abe, M.; Seto, M.; Gogliotti, R.G.; Loch, M.T.; Bollinger, K.A.; Chang, S.; Engelberg, E.M.; Luscombe, V.B.; Harp, J.M.; Bubser, M.; Engers, D.W.; Jones, C.K.; Rodriguez, A.L.; Blobaum, A.L.; Conn, P.J.; Niswender, C.M.; Lindsley, C.W. Discovery of VU6005649, a CNS penetrant mGlu7/8 Receptor PAM derived from a series of pyrazolo[1,5-a]pyrimidines. ACS Med. Chem. Lett., 2017, 8(10), 1110-1115.
[] [PMID: 29057060]
Jalan-Sakrikar, N.; Field, J.R.; Klar, R.; Mattmann, M.E.; Gregory, K.J.; Zamorano, R.; Engers, D.W.; Bollinger, S.R.; Weaver, C.D.; Days, E.L.; Lewis, L.M.; Utley, T.J.; Hurtado, M.; Rigault, D.; Acher, F.; Walker, A.G.; Melancon, B.J.; Wood, M.R.; Lindsley, C.W.; Conn, P.J.; Xiang, Z.; Hopkins, C.R.; Niswender, C.M. Identification of positive allosteric modulators VU0155094 (ML397) and VU0422288 (ML396) reveals new insights into the biology of metabotropic glutamate receptor 7. ACS Chem. Neurosci., 2014, 5(12), 1221-1237.
[] [PMID: 25225882]
Kalinichev, M.; Rouillier, M.; Girard, F.; Royer-Urios, I.; Bournique, B.; Finn, T.; Charvin, D.; Campo, B.; Le Poul, E.; Mutel, V.; Poli, S.; Neale, S.A.; Salt, T.E.; Lütjens, R. ADX71743, a potent and selective negative allosteric modulator of metabotropic glutamate receptor 7: in vitro and in vivo characterization. J. Pharmacol. Exp. Ther., 2013, 344(3), 624-636.
[] [PMID: 23257312]
Tresadern, G.; Trabanco, A.A.; Pérez-Benito, L.; Overington, J.P.; van Vlijmen, H.W.T.; van Westen, G.J.P. Identification of allosteric modulators of metabotropic glutamate 7 receptor using proteochemometric modeling. J. Chem. Inf. Model., 2017, 57(12), 2976-2985.
[] [PMID: 29172488]
Salih, H.; Anghelescu, I.; Kezic, I.; Sinha, V.; Hoeben, E.; Van Nueten, L.; De Smedt, H.; De Boer, P. Pharmacokinetic and pharmacodynamic characterisation of JNJ-40411813, a positive allosteric modulator of mGluR2, in two randomised, double-blind phase-I studies. J. Psychopharmacol. (Oxford), 2015, 29(4), 414-425.
[] [PMID: 25735992]
Tison, F.; Keywood, C.; Wakefield, M.; Durif, F.; Corvol, J.C.; Eggert, K.; Lew, M.; Isaacson, S.; Bezard, E.; Poli, S.M.; Goetz, C.G.; Trenkwalder, C.; Rascol, O. A phase 2A trial of the novel mGlur5-negative allosteric modulator dipraglurant for levodopa-induced dyskinesia in parkinson’s disease. Mov. Disord., 2016, 31(9), 1373-1380.
[] [PMID: 27214664]
Bailey, D.B., Jr; Berry-Kravis, E.; Wheeler, A.; Raspa, M.; Merrien, F.; Ricart, J.; Koumaras, B.; Rosenkranz, G.; Tomlinson, M.; von Raison, F.; Apostol, G. Mavoglurant in adolescents with fragile X syndrome: analysis of Clinical Global Impression-Improvement source data from a double-blind therapeutic study followed by an open-label, long-term extension study. J. Neurodev. Disord., 2016, 8, 1.
[] [PMID: 26855682]
Berry-Kravis, E.; Des Portes, V.; Hagerman, R.; Jacquemont, S.; Charles, P.; Visootsak, J.; Brinkman, M.; Rerat, K.; Koumaras, B.; Zhu, L.; Barth, G.M.; Jaecklin, T.; Apostol, G.; von Raison, F. Mavoglurant in fragile X syndrome: Results of two randomized, double-blind, placebo-controlled trials. Sci. Transl. Med., 2016, 8(321)321ra5
[] [PMID: 26764156]
Hagerman, R.; Jacquemont, S.; Berry-Kravis, E.; Des Portes, V.; Stanfield, A.; Koumaras, B.; Rosenkranz, G.; Murgia, A.; Wolf, C.; Apostol, G.; von Raison, F. Mavoglurant in Fragile X Syndrome: Results of two open-label, extension trials in adults and adolescents. Sci. Rep., 2018, 8(1), 16970.
[] [PMID: 30451888]
Kumar, R.; Hauser, R.A.; Mostillo, J.; Dronamraju, N.; Graf, A.; Merschhemke, M.; Kenney, C. Mavoglurant (AFQ056) in combination with increased levodopa dosages in Parkinson’s disease patients. Int. J. Neurosci., 2016, 126(1), 20-24.
[] [PMID: 24007304]
Rutrick, D.; Stein, D.J.; Subramanian, G.; Smith, B.; Fava, M.; Hasler, G.; Cha, J.H.; Gasparini, F.; Donchev, T.; Ocwieja, M.; Johns, D.; Gomez-Mancilla, B. Mavoglurant Augmentation in OCD Patients Resistant to Selective Serotonin Reuptake Inhibitors: A Proof-of-Concept, Randomized, Placebo-Controlled, Phase 2 Study. Adv. Ther., 2017, 34(2), 524-541.
[] [PMID: 28044255]
Trenkwalder, C.; Stocchi, F.; Poewe, W.; Dronamraju, N.; Kenney, C.; Shah, A.; von Raison, F.; Graf, A. Mavoglurant in Parkinson’s patients with l-Dopa-induced dyskinesias: Two randomized phase 2 studies. Mov. Disord., 2016, 31(7), 1054-1058.
[] [PMID: 27214258]
Quiroz, J.A.; Tamburri, P.; Deptula, D.; Banken, L.; Beyer, U.; Rabbia, M.; Parkar, N.; Fontoura, P.; Santarelli, L. Efficacy and safety of basimglurant as adjunctive therapy for major depression: a randomized clinical trial. JAMA Psychiatry, 2016, 73(7), 675-684.
[] [PMID: 27304433]
Youssef, E.A.; Berry-Kravis, E.; Czech, C.; Hagerman, R.J.; Hessl, D.; Wong, C.Y.; Rabbia, M.; Deptula, D.; John, A.; Kinch, R.; Drewitt, P.; Lindemann, L.; Marcinowski, M.; Langland, R.; Horn, C.; Fontoura, P.; Santarelli, L.; Quiroz, J.A. Effect of the mGluR5-NAM basimglurant on behavior in adolescents and adults with fragile X syndrome in a randomized, double-blind, placebo-controlled trial: fragXis phase 2 results. Neuropsychopharmacology, 2018, 43(3), 503-512.
[] [PMID: 28816242]
Keywood, C.; Wakefield, M.; Tack, J. A proof-of-concept study evaluating the effect of ADX10059, a metabotropic glutamate receptor-5 negative allosteric modulator, on acid exposure and symptoms in gastro-oesophageal reflux disease. Gut, 2009, 58(9), 1192-1199.
[] [PMID: 19460767]
Zerbib, F.; Bruley des Varannes, S.; Roman, S.; Tutuian, R.; Galmiche, J.P.; Mion, F.; Tack, J.; Malfertheiner, P.; Keywood, C. Randomised clinical trial: effects of monotherapy with ADX10059, a mGluR5 inhibitor, on symptoms and reflux events in patients with gastro-oesophageal reflux disease. Aliment. Pharmacol. Ther., 2011, 33(8), 911-921.
[] [PMID: 21320138]
Wenthur, C.J.; Gentry, P.R.; Mathews, T.P.; Lindsley, C.W. Drugs for allosteric sites on receptors. Annu. Rev. Pharmacol. Toxicol., 2014, 54, 165-184.
[] [PMID: 24111540]
Hanyaloglu, A.C.; Grammatopoulos, D.K. Pleiotropic GPCR signaling in health and disease. Mol. Cell. Endocrinol., 2017, 449, 1-2.
[] [PMID: 28528660]
Dobrovetsky, E.; Dong, A.; Hutchinson, A.; Tempel, W.; Edwards, A. M.; Bountra, C.; Arrowsmith, C. H. Human metabotropic glutamate receptor 7, extracellular ligand binding domain. Structural Genomics Consortium (SGC), 2015.PDB ID5C5C.
Dobrovetsky, E.; Khutoreskaya, G.; Seitova, A.; Cossar, D.; Edwards, A. M.; Arrowsmith, C. H.; Bountra, C.; Weigelt, J.; Bochkarev, A. Metabotropic glutamate receptor mGluR1 complexed with LY341495 antagonist. Structural Genomics Consortium (SGC), 2009.PDB ID, 3KS9.
Dobrovetsky, E.; Khutoreskaya, G.; Seitova, A.; Cossar, D.; Edwards, A. M.; Arrowsmith, C. H.; Bountra, C.; Weigelt, J.; Bochkarev, A. Metabotropic glutamate receptor mGluR5 complexed with glutamate. Structural Genomics Consortium (SGC), 2010.PDB ID, 3LMK.
Dobrovetsky, E.; Khutoreskaya, G.; Seitova, A.; He, H.; Weigelt, J.; Edwards, A. M.; Arrowsmith, C. H.; Bountra, C.; Cossar, D.; Bochkarev, A. mGluR7 complexed with LY341495. Structural Genomics Consortium (SGC) 2010, PDB ID: 3MQ4.
Muto, T.; Tsuchiya, D.; Morikawa, K.; Jingami, H. Structures of the extracellular regions of the group II/III metabotropic glutamate receptors. Proc. Natl. Acad. Sci. USA, 2007, 104, 3759-3764.
Schkeryantz, J.M.; Chen, Q.; Ho, J.D.; Atwell, S.; Zhang, A.; Vargas, M.C.; Wang, J.; Monn, J.A.; Hao, J. Determination of L-AP4-bound human mGlu8 receptor amino terminal domain structure and the molecular basis for L-AP4's group III mGlu receptor functional potency and selectivity. Bioorg. Med. Chem. Lett., 2018, 28(4), 612-617.
[] [PMID: 29402739]
Tsuchiya, D.; Kunishima, N.; Kamiya, N.; Jingami, H.; Morikawa, K. Structural views of the ligand-binding cores of a metabotropic glutamate receptor complexed with an antagonist and both glutamate and Gd3+. Proc. Natl. Acad. Sci. USA, 2002, 99(5), 2660-2665.
[] [PMID: 11867751]
Wernimont, A. K.; Dong, A.; Seitova, A.; Crombet, L.; Khutoreskaya, G.; Edwards, A. M.; Arrowsmith, C. H.; Bountra, C.; Weigelt, J.; Cossar, D.; Dobrovetsky, E. Crystal structure of metabotropic glutamate receptor 3 precursor in presence of LY341495 antagonist. Structural Genomics Consortium (SGC), 2011.PDB ID, 3SM9.
Chen, Q.; Ho, J.D.; Ashok, S.; Vargas, M.C.; Wang, J.; Atwell, S.; Bures, M.; Schkeryantz, J.M.; Monn, J.A.; Hao, J. Structural basis for (S)-3,4-Dicarboxyphenylglycine (DCPG) as a potent and subtype selective agonist of the mglu8 receptor. J. Med. Chem., 2018, 61(22), 10040-10052.
[] [PMID: 30365309]
Berman, H.M.; Westbrook, J.; Feng, Z.; Gilliland, G.; Bhat, T.N.; Weissig, H.; Shindyalov, I.N.; Bourne, P.E. The protein data bank. Nucleic Acids Res., 2000, 28(1), 235-242.
[] [PMID: 10592235]
Chemical Computing Group. Molecular Operating Environment (MOE), Version 2016: Montreal, QC, Canada, 2016. (Accessed
Sekiyama, N.; Hayashi, Y.; Nakanishi, S.; Jane, D.E.; Tse, H.W.; Birse, E.F.; Watkins, J.C. Structure-activity relationships of new agonists and antagonists of different metabotropic glutamate receptor subtypes. Br. J. Pharmacol., 1996, 117(7), 1493-1503.
[] [PMID: 8730745]
Bessis, A-S.; Rondard, P.; Gaven, F.; Brabet, I.; Triballeau, N.; Prézeau, L.; Acher, F.; Pin, J-P. Closure of the Venus flytrap module of mGlu8 receptor and the activation process: Insights from mutations converting antagonists into agonists. Proc. Natl. Acad. Sci. USA, 2002, 99(17), 11097-11102.
[] [PMID: 12151600]
Kammermeier, P.J. Constitutive activity of metabotropic glutamate receptor 7. BMC Neurosci., 2015, 16, 17.
[] [PMID: 25881041]
Lavezzari, G.; Roche, K.W. Constitutive endocytosis of the metabotropic glutamate receptor mGluR7 is clathrin-independent. Neuropharmacology, 2007, 52(1), 100-107.
[] [PMID: 16890965]
Kniazeff, J.; Bessis, A-S.; Maurel, D.; Ansanay, H.; Prézeau, L.; Pin, J-P. Closed state of both binding domains of homodimeric mGlu receptors is required for full activity. Nat. Struct. Mol. Biol., 2004, 11(8), 706-713.
[] [PMID: 15235591]
Yanagawa, M.; Yamashita, T.; Shichida, Y. Comparative fluorescence resonance energy transfer analysis of metabotropic glutamate receptors: implications about the dimeric arrangement and rearrangement upon ligand bindings. J. Biol. Chem., 2011, 286(26), 22971-22981.
[] [PMID: 21550987]

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Article Details

Year: 2019
Published on: 10 December, 2019
Page: [2421 - 2446]
Pages: 26
DOI: 10.2174/1568026619666191011094935

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