Fragment-Based Approaches for Allosteric Metabotropic Glutamate Receptor (mGluR) Modulators

Author(s): Zoltán Orgován, György G. Ferenczy, György M. Keserű*.

Journal Name: Current Topics in Medicinal Chemistry

Volume 19 , Issue 19 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Metabotropic glutamate receptors (mGluR) are members of the class C G-Protein Coupled Receptors (GPCR-s) and have eight subtypes. These receptors are responsible for a variety of functions in the central and peripheral nervous systems and their modulation has therapeutic utility in neurological and psychiatric disorders. It was previously established that selective orthosteric modulation of these receptors is challenging, and this stimulated the search for allosteric modulators. Fragment-Based Drug Discovery (FBDD) is a viable approach to find ligands binding at allosteric sites owing to their limited size and interactions. However, it was also observed that the structure-activity relationship of allosteric modulators is often sharp and inconsistent. This can be attributed to the characteristics of the allosteric binding site of mGluRs that is a water channel where ligand binding is accompanied with induced fit and interference with the water network, both playing a role in receptor activation. In this review, we summarize fragment-based drug discovery programs on mGluR allosteric modulators and their contribution identifying of new mGluR ligands with better activity and selectivity.

Keywords: Metabotropic glutamate receptors, GPCR, Fragment-based drug discovery, Allosteric modulators, Glutamate binding site, Cysteine rich domain.

[1]
Dingledine, R.; Borges, K.; Bowie, D.; Traynelis, S.F. The glutamate receptor ion channels. Pharmacol. Rev., 1999, 51(1), 7-61.
[PMID: 10049997]
[2]
Sugiyama, H.; Ito, I.; Hirono, C. A new type of glutamate receptor linked to inositol phospholipid metabolism. Nature, 1987, 325(6104), 531-533.
[http://dx.doi.org/10.1038/325531a0] [PMID: 2880300]
[3]
Niswender, C.M.; Conn, P.J. Metabotropic glutamate receptors: Physiology, pharmacology, and disease. Annu. Rev. Pharmacol. Toxicol., 2010, 50, 295-322.
[http://dx.doi.org/10.1146/annurev.pharmtox.011008.145533] [PMID: 20055706]
[4]
Pin, J.P.; Acher, F. The metabotropic glutamate receptors: structure, activation mechanism and pharmacology. Curr. Drug Targets CNS Neurol. Disord., 2002, 1(3), 297-317.
[http://dx.doi.org/10.2174/1568007023339328] [PMID: 12769621]
[5]
Récasens, M.; Guiramand, J.; Aimar, R.; Abdulkarim, A.; Barbanel, G. Metabotropic glutamate receptors as drug targets. Curr. Drug Targets, 2007, 8(5), 651-681.
[http://dx.doi.org/10.2174/138945007780618544] [PMID: 17504108]
[6]
Gregory, K.J.; Dong, E.N.; Meiler, J.; Conn, P.J. Allosteric modulation of metabotropic glutamate receptors: Structural insights and therapeutic potential. Neuropharmacology, 2011, 60(1), 66-81.
[http://dx.doi.org/10.1016/j.neuropharm.2010.07.007] [PMID: 20637216]
[7]
Jean-Charles, P-Y.; Kaur, S.; Shenoy, S.K.G.G. Protein-coupled receptor signaling through β-arrestin-dependent mechanisms. J. Cardiovasc. Pharmacol., 2017, 70(3), 142-158.
[http://dx.doi.org/10.1097/FJC.0000000000000482] [PMID: 28328745]
[8]
Pin, J.P.; Galvez, T.; Prézeau, L. Evolution, structure, and activation mechanism of family 3/C G-protein-coupled receptors. Pharmacol. Ther., 2003, 98(3), 325-354.
[http://dx.doi.org/10.1016/S0163-7258(03)00038-X] [PMID: 12782243]
[9]
Bräuner-Osborne, H.; Wellendorph, P.; Jensen, A.A. Structure, pharmacology and therapeutic prospects of family C G-protein coupled receptors. Curr. Drug Targets, 2007, 8(1), 169-184.
[http://dx.doi.org/10.2174/138945007779315614] [PMID: 17266540]
[10]
Hinoi, E.; Ogita, K.; Takeuchi, Y.; Ohashi, H.; Maruyama, T.; Yoneda, Y. Characterization with [3H]quisqualate of group I metabotropic glutamate receptor subtype in rat central and peripheral excitable tissues. Neurochem. Int., 2001, 38(3), 277-285.
[http://dx.doi.org/10.1016/S0197-0186(00)00075-9] [PMID: 11099787]
[11]
Endoh, T. Characterization of modulatory effects of postsynaptic metabotropic glutamate receptors on calcium currents in rat nucleus tractus solitarius. Brain Res., 2004, 1024(1-2), 212-224.
[http://dx.doi.org/10.1016/j.brainres.2004.07.074] [PMID: 15451384]
[12]
Hermans, E.; Challiss, R.A.J. Structural, signalling and regulatory properties of the group I metabotropic glutamate receptors: prototypic family C G-protein-coupled receptors. Biochem. J., 2001, 359(Pt 3), 465-484.
[http://dx.doi.org/10.1042/bj3590465] [PMID: 11672421]
[13]
Saugstad, J.A.; Ingram, S.L. Group I Metabotropic glutamate receptors (MGlu1 and MGlu5). The glutamate receptors; Swanson, G; Gereau, R.W., Ed.; Humana Press Inc: Totowa, NJ, 2008, pp. 387-463.
[http://dx.doi.org/10.1007/978-1-59745-055-3_10]
[14]
Johnson, M.P.; Schoepp, D.D. Group II metabotropic glutamate receptors and schizophrenia. The glutamate receptors; Gereau, R.W; Swanson, G., Ed.; Humana Press Inc: Totowa, NJ, 2008, pp. 465-488.
[http://dx.doi.org/10.1007/978-1-59745-055-3_11]
[15]
Neugebauer, V. Group III Metabotropic glutamate receptors (MGlu4, MGlu6, MGlu7, and MGlu8). The glutamate receptors; Gereau, R.W; Swanson, G., Ed.; Humana Press Inc: Totowa, NJ, 2008, pp. 489-508.
[http://dx.doi.org/10.1007/978-1-59745-055-3_12]
[16]
Dalton, J.A.R.; Gómez-Santacana, X.; Llebaria, A.; Giraldo, J. Computational analysis of negative and positive allosteric modulator binding and function in metabotropic glutamate receptor 5 (in)activation. J. Chem. Inf. Model., 2014, 54(5), 1476-1487.
[http://dx.doi.org/10.1021/ci500127c] [PMID: 24793143]
[17]
Mølck, C.; Harpsøe, K.; Gloriam, D.E.; Mathiesen, J.M.; Nielsen, S.M.; Bräuner-Osborne, H. mGluR5: Exploration of orthosteric and allosteric ligand binding pockets and their applications to drug discovery. Neurochem. Res., 2014, 39(10), 1862-1875.
[http://dx.doi.org/10.1007/s11064-014-1248-8] [PMID: 24493625]
[18]
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(10), 3759-3764.
[http://dx.doi.org/10.1073/pnas.0611577104] [PMID: 17360426]
[19]
Kniazeff, J.; Prézeau, L.; Rondard, P.; Pin, J-P.; Goudet, C. Dimers and beyond: The functional puzzles of class C GPCRs. Pharmacol. Ther., 2011, 130(1), 9-25.
[http://dx.doi.org/10.1016/j.pharmthera.2011.01.006] [PMID: 21256155]
[20]
Pin, J-P.; De Colle, C.; Bessis, A-S.; Acher, F. New perspectives for the development of selective metabotropic glutamate receptor ligands. Eur. J. Pharmacol., 1999, 375(1-3), 277-294.
[http://dx.doi.org/10.1016/S0014-2999(99)00258-7] [PMID: 10443583]
[21]
Flor, P.J.; Acher, F.C. Orthosteric versus allosteric GPCR activation: The great challenge of group-III mGluRs. Biochem. Pharmacol., 2012, 84(4), 414-424.
[http://dx.doi.org/10.1016/j.bcp.2012.04.013] [PMID: 22554564]
[22]
Burford, N.T.; Watson, J.; Bertekap, R.; Alt, A. Strategies for the identification of allosteric modulators of G-protein-coupled receptors. Biochem. Pharmacol., 2011, 81(6), 691-702.
[http://dx.doi.org/10.1016/j.bcp.2010.12.012] [PMID: 21184747]
[23]
Conn, P.J.; Christopoulos, A.; Lindsley, C.W. Allosteric modulators of GPCRs: A novel approach for the treatment of CNS disorders. Nat. Rev. Drug Discov., 2009, 8(1), 41-54.
[http://dx.doi.org/10.1038/nrd2760] [PMID: 19116626]
[24]
Lindsley, C.W.; Emmitte, K.A.; Hopkins, C.R.; Bridges, T.M.; Gregory, K.J.; Niswender, C.M.; Conn, P.J. Practical strategies and concepts in GPCR allosteric modulator discovery: Recent advances with metabotropic glutamate receptors. Chem. Rev., 2016, 116(11), 6707-6741.
[http://dx.doi.org/10.1021/acs.chemrev.5b00656] [PMID: 26882314]
[25]
Harpsøe, K.; Isberg, V.; Tehan, B.G.; Weiss, D.; Arsova, A.; Marshall, F.H.; Bräuner-Osborne, H.; Gloriam, D.E. Selective negative allosteric modulation of metabotropic glutamate receptors - A structural perspective of ligands and mutants. Sci. Rep., 2015, 5, 13869.
[http://dx.doi.org/10.1038/srep13869] [PMID: 26359761]
[26]
Christopher, J.A.; Orgován, Z.; Congreve, M.; Doré, A.S.; Errey, J.C.; Marshall, F.H.; Mason, J.S.; Okrasa, K.; Rucktooa, P.; Serrano-Vega, M.J.; Ferenczy, G.G.; Keserű, G.M. Structure-based optimization strategies for G protein-coupled receptor (GPCR) allosteric modulators: A case study from analyses of new metabotropic glutamate receptor 5 (mGlu5) X-ray structures. J. Med. Chem., 2019, 62(1), 207-222.
[http://dx.doi.org/10.1021/acs.jmedchem.7b01722] [PMID: 29455526]
[27]
Rettenmaier, J.T.; Hudson, S.A.; Wells, J.A. Site-Directed Fragment Discovery for Allostery.In:Fragment-based drug discovery: lessons and outlook; Erlanson, D.A.; Jahnke, W., Eds. . Wiley- VCH, 2016, pp. 247-266.
[http://dx.doi.org/10.1002/9783527683604.ch11]
[28]
Daniel, A.E. Introduction to fragment-based drug discovery. fragment-based drug discovery and X-Ray crystallography; Davies, T; Hyvönen, M., Ed.; Springer: Berlin, Heidelberg, 2011, pp. 1-32.
[29]
Gasparini, F.; Spooren, W. Allosteric modulators for mGlu receptors. Curr. Neuropharmacol., 2007, 5(3), 187-194.
[http://dx.doi.org/10.2174/157015907781695900] [PMID: 19305801]
[30]
Urwyler, S. Allosteric modulation of family C G-protein-coupled receptors: From molecular insights to therapeutic perspectives. Pharmacol. Rev., 2011, 63(1), 59-126.
[http://dx.doi.org/10.1124/pr.109.002501] [PMID: 21228259]
[31]
Lesage, A.; Steckler, T. Metabotropic glutamate mGlu1 receptor stimulation and blockade: Therapeutic opportunities in psychiatric illness. Eur. J. Pharmacol., 2010, 639(1-3), 2-16.
[http://dx.doi.org/10.1016/j.ejphar.2009.12.043] [PMID: 20371230]
[32]
Litschig, S.; Gasparini, F.; Rueegg, D.; Stoehr, N.; Flor, P.J.; Vranesic, I.; Prézeau, L.; Pin, J.P.; Thomsen, C.; Kuhn, R. CPCCOEt, a noncompetitive metabotropic glutamate receptor 1 antagonist, inhibits receptor signaling without affecting glutamate binding. Mol. Pharmacol., 1999, 55(3), 453-461.
[PMID: 10051528]
[33]
Annoura, H.; Fukunaga, A.; Uesugi, M.; Tatsuoka, T.; Horikawa, Y. A novel class of antagonists for metabotropic glutamate re-ceptors, 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylates. Bioorg. Med. Chem. Lett., 1996, 6, 763-766.
[http://dx.doi.org/10.1016/0960-894X(96)00104-7]
[34]
Hermans, E.; Nahorski, S.R.; Challiss, R.A. Reversible and non-competitive antagonist profile of CPCCOEt at the human type 1α metabotropic glutamate receptor. Neuropharmacology, 1998, 37(12), 1645-1647.
[http://dx.doi.org/10.1016/S0028-3908(98)00132-4] [PMID: 9886688]
[35]
Schann, S.; Mayer, S.; Franchet, C.; Frauli, M.; Steinberg, E.; Thomas, M.; Baron, L.; Neuville, P. Chemical switch of a metabotropic glutamate receptor 2 silent allosteric modulator into dual metabotropic glutamate receptor 2/3 negative/positive allosteric modulators. J. Med. Chem., 2010, 53(24), 8775-8779.
[http://dx.doi.org/10.1021/jm101069m] [PMID: 21105727]
[36]
Carroll, F.Y.; Stolle, A.; Beart, P.M.; Voerste, A.; Brabet, I.; Mauler, F.; Joly, C.; Antonicek, H.; Bockaert, J.; Müller, T.; Pin, J.P.; Prézeau, L. BAY36-7620: A potent non-competitive mGlu1 receptor antagonist with inverse agonist activity. Mol. Pharmacol., 2001, 59(5), 965-973.
[http://dx.doi.org/10.1124/mol.59.5.965] [PMID: 11306677]
[37]
Cho, H.P.; Engers, D.W.; Venable, D.F.; Niswender, C.M.; Lindsley, C.W.; Conn, P.J.; Emmitte, K.A.; Rodriguez, A.L. A novel class of succinimide-derived negative allosteric modulators of metabotropic glutamate receptor subtype 1 provides insight into a disconnect in activity between the rat and human receptors. ACS Chem. Neurosci., 2014, 5(7), 597-610.
[http://dx.doi.org/10.1021/cn5000343] [PMID: 24798819]
[38]
Shannon, H.E.; Peters, S.C.; Kingston, A.E. Anticonvulsant effects of LY456236, a selective mGlu1 receptor antagonist. Neuropharmacology, 2005, 49(Suppl. 1), 188-195.
[http://dx.doi.org/10.1016/j.neuropharm.2005.05.010] [PMID: 16011839]
[39]
Di Fabio, R.; Micheli, F.; Alvaro, G.; Cavanni, P.; Donati, D.; Gagliardi, T.; Fontana, G.; Giovannini, R.; Maffeis, M.; Mingardi, A.; Tranquillini, M.E.; Vitulli, G. From pyrroles to 1-oxo-2,3,4,9-tetrahydro-1H-β-carbolines: a new class of orally bioavailable mGluR1 antagonists. Bioorg. Med. Chem. Lett., 2007, 17(8), 2254-2259.
[http://dx.doi.org/10.1016/j.bmcl.2007.01.055] [PMID: 17276684]
[40]
Lavreysen, H.; Wouters, R.; Bischoff, F.; Nóbrega Pereira, S.; Langlois, X.; Blokland, S.; Somers, M.; Dillen, L.; Lesage, A.S.J. JNJ16259685, a highly potent, selective and systemically active mGlu1 receptor antagonist. Neuropharmacology, 2004, 47(7), 961-972.
[http://dx.doi.org/10.1016/j.neuropharm.2004.08.007] [PMID: 15555631]
[41]
Satoh, A.; Nagatomi, Y.; Hirata, Y.; Ito, S.; Suzuki, G.; Kimura, T.; Maehara, S.; Hikichi, H.; Satow, A.; Hata, M.; Ohta, H.; Kawamoto, H. Discovery and in vitro and in vivo profiles of 4-fluoro-N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methylbenzamide as novel class of an orally active metabotropic glutamate receptor 1 (mGluR1) antagonist. Bioorg. Med. Chem. Lett., 2009, 19(18), 5464-5468.
[http://dx.doi.org/10.1016/j.bmcl.2009.07.097] [PMID: 19674894]
[42]
Ito, S.; Hirata, Y.; Nagatomi, Y.; Satoh, A.; Suzuki, G.; Kimura, T.; Satow, A.; Maehara, S.; Hikichi, H.; Hata, M.; Ohta, H.; Kawamoto, H. Discovery and biological profile of isoindolinone derivatives as novel metabotropic glutamate receptor 1 antagonists: a potential treatment for psychotic disorders. Bioorg. Med. Chem. Lett., 2009, 19(18), 5310-5313.
[http://dx.doi.org/10.1016/j.bmcl.2009.07.145] [PMID: 19692242]
[43]
Steckler, T.; Lavreysen, H.; Oliveira, A.M.; Aerts, N.; Van Craenendonck, H.; Prickaerts, J.; Megens, A.; Lesage, A.S.J. Effects of mGlu1 receptor blockade on anxiety-related behaviour in the rat lick suppression test. Psychopharmacology (Berl.), 2005, 179(1), 198-206.
[http://dx.doi.org/10.1007/s00213-004-2056-7] [PMID: 15821950]
[44]
Kew, J.N.C. Positive and negative allosteric modulation of metabotropic glutamate receptors: emerging therapeutic potential. Pharmacol. Ther., 2004, 104(3), 233-244.
[http://dx.doi.org/10.1016/j.pharmthera.2004.08.010] [PMID: 15556676]
[45]
Sabbatini, F.M.; Micheli, F. Metabotropic glutamate receptors: Potential therapeutic applications of recently disclosed new chemical entities. Expert Opin. Ther. Pat., 2004, 14, 1593-1604.
[http://dx.doi.org/10.1517/13543776.14.11.1593]
[46]
Knoflach, F.; Mutel, V.; Jolidon, S.; Kew, J.N.C.; Malherbe, P.; Vieira, E.; Wichmann, J.; Kemp, J.A. Positive allosteric modulators of metabotropic glutamate 1 receptor: characterization, mechanism of action, and binding site. Proc. Natl. Acad. Sci. USA, 2001, 98(23), 13402-13407.
[http://dx.doi.org/10.1073/pnas.231358298] [PMID: 11606768]
[47]
Hemstapat, K.; de Paulis, T.; Chen, Y.; Brady, A.E.; Grover, V.K.; Alagille, D.; Tamagnan, G.D.; Conn, P.J. A novel class of positive allosteric modulators of metabotropic glutamate receptor subtype 1 interact with a site distinct from that of negative allosteric modulators. Mol. Pharmacol., 2006, 70(2), 616-626.
[http://dx.doi.org/10.1124/mol.105.021857] [PMID: 16645124]
[48]
Gasparini, F.; Andres, H.; Flor, P.J.; Heinrich, M.; Inderbitzin, W.; Lingenhöhl, K.; Müller, H.; Munk, V.C.; Omilusik, K.; Stierlin, C.; Stoehr, N.; Vranesic, I.; Kuhn, R. [(3)H]-M-MPEP, a potent, subtype-selective radioligand for the metabotropic glutamate receptor subtype 5. Bioorg. Med. Chem. Lett., 2002, 12(3), 407-409.
[http://dx.doi.org/10.1016/S0960-894X(01)00767-3] [PMID: 11814808]
[49]
Montana, M.C.; Cavallone, L.F.; Stubbert, K.K.; Stefanescu, A.D.; Kharasch, E.D.; Gereau, R.W., IV The metabotropic glutamate receptor subtype 5 antagonist fenobam is analgesic and has improved in vivo selectivity compared with the prototypical antagonist 2-methyl-6-(phenylethynyl)-pyridine. J. Pharmacol. Exp. Ther., 2009, 330(3), 834-843.
[http://dx.doi.org/10.1124/jpet.109.154138] [PMID: 19515968]
[50]
Jaeschke, G.; Wettstein, J.G.; Nordquist, R.E.; Spooren, W. MGlu5 Receptor antagonists and their therapeutic potential. Expert Opin. Ther. Pat., 2008, 18, 123-142.
[http://dx.doi.org/10.1517/13543776.18.2.123]
[51]
Slassi, A.; Isaac, M.; Edwards, L.; Minidis, A.; Wensbo, D.; Mattsson, J.; Nilsson, K.; Raboisson, P.; McLeod, D.; Stormann, T.M.; Hammerland, L.G.; Johnson, E. Recent advances in non-competitive mGlu5 receptor antagonists and their potential therapeutic applications. Curr. Top. Med. Chem., 2005, 5(9), 897-911.
[http://dx.doi.org/10.2174/1568026054750236] [PMID: 16178734]
[52]
Varney, M.A.; Cosford, N.D.; Jachec, C.; Rao, S.P.; Sacaan, A.; Lin, F.F.; Bleicher, L.; Santori, E.M.; Flor, P.J.; Allgeier, H.; Gasparini, F.; Kuhn, R.; Hess, S.D.; Veliçelebi, G.; Johnson, E.C. SIB-1757 and SIB-1893: selective, noncompetitive antagonists of metabotropic glutamate receptor type 5. J. Pharmacol. Exp. Ther., 1999, 290(1), 170-181.
[PMID: 10381773]
[53]
Gasparini, F.; Lingenhöhl, K.; Stoehr, N.; Flor, P.J.; Heinrich, M.; Vranesic, I.; Biollaz, M.; Allgeier, H.; Heckendorn, R.; Urwyler, S.; Varney, M.A.; Johnson, E.C.; Hess, S.D.; Rao, S.P.; Sacaan, A.I.; Santori, E.M.; Veliçelebi, G.; Kuhn, R. 2-Methyl-6-(phenylethynyl)-pyridine (MPEP), a potent, selective and systemically active mGlu5 receptor antagonist. Neuropharmacology, 1999, 38(10), 1493-1503.
[http://dx.doi.org/10.1016/S0028-3908(99)00082-9] [PMID: 10530811]
[54]
Milbank, J.B.J.; Knauer, C.S.; Augelli-Szafran, C.E.; Sakkab-Tan, A.T.; Lin, K.K.; Yamagata, K.; Hoffman, J.K.; Zhuang, N.; Thomas, J.; Galatsis, P.; Wendt, J.A.; Mickelson, J.W.; Schwarz, R.D.; Kinsora, J.J.; Lotarski, S.M.; Stakich, K.; Gillespie, K.K.; Lam, W.W.; Mutlib, A.E. Rational design of 7-arylquinolines as non-competitive metabotropic glutamate receptor subtype 5 antagonists. Bioorg. Med. Chem. Lett., 2007, 17(16), 4415-4418.
[http://dx.doi.org/10.1016/j.bmcl.2007.06.030] [PMID: 17590335]
[55]
Cosford, N.D.P.; Tehrani, L.; Roppe, J.; Schweiger, E.; Smith, N.D.; Anderson, J.; Bristow, L.; Brodkin, J.; Jiang, X.; McDonald, I.; Rao, S.; Washburn, M.; Varney, M.A. 3-[(2-Methyl-1,3-thiazol-4-yl)ethynyl]-pyridine: a potent and highly selective metabotropic glutamate subtype 5 receptor antagonist with anxiolytic activity. J. Med. Chem., 2003, 46(2), 204-206.
[http://dx.doi.org/10.1021/jm025570j] [PMID: 12519057]
[56]
Cosford, N.D.; Roppe, J.; Tehrani, L.; Schweiger, E.J.; Seiders, T.J.; Chaudary, A.; Rao, S.; Varney, M.A. [3H]-methoxymethyl-MTEP and [3H]-methoxy-PEPy: potent and selective radioligands for the metabotropic glutamate subtype 5 (mGlu5) receptor. Bioorg. Med. Chem. Lett., 2003, 13(3), 351-354.
[http://dx.doi.org/10.1016/S0960-894X(02)00997-6] [PMID: 12565928]
[57]
Siméon, F.G.; Brown, A.K.; Zoghbi, S.S.; Patterson, V.M.; Innis, R.B.; Pike, V.W. Synthesis and simple 18F-labeling of 3-fluoro-5-(2-(2-(fluoromethyl)thiazol-4-yl)ethynyl)benzonitrile as a high affinity radioligand for imaging monkey brain metabotropic glutamate subtype-5 receptors with positron emission tomography. J. Med. Chem., 2007, 50(14), 3256-3266.
[http://dx.doi.org/10.1021/jm0701268] [PMID: 17571866]
[58]
Rocher, J-P.; Bonnet, B.; Boléa, C.; Lütjens, R.; Le Poul, E.; Poli, S.; Epping-Jordan, M.; Bessis, A-S.; Ludwig, B.; Mutel, V. mGluR5 negative allosteric modulators overview: a medicinal chemistry approach towards a series of novel therapeutic agents. Curr. Top. Med. Chem., 2011, 11(6), 680-695.
[http://dx.doi.org/10.2174/1568026611109060680] [PMID: 21261592]
[59]
Dekundy, A.; Gravius, A.; Hechenberger, M.; Pietraszek, M.; Nagel, J.; Tober, C.; van der Elst, M.; Mela, F.; Parsons, C.G.; Danysz, W. Pharmacological characterization of MRZ-8676, a novel negative allosteric modulator of subtype 5 metabotropic glutamate receptors (mGluR5): focus on L: -DOPA-induced dyskinesia. J. Neural Transm. (Vienna), 2011, 118(12), 1703-1716.
[http://dx.doi.org/10.1007/s00702-010-0526-0] [PMID: 21161716]
[60]
Sharma, S.; Kedrowski, J.; Rook, J.M.; Smith, R.L.; Jones, C.K.; Rodriguez, A.L.; Conn, P.J.; Lindsley, C.W. Discovery of molecular switches that modulate modes of metabotropic glutamate receptor subtype 5 (mGlu5) pharmacology in vitro and in vivo within a series of functionalized, regioisomeric 2- and 5-(phenylethynyl)pyrimidines. J. Med. Chem., 2009, 52(14), 4103-4106.
[http://dx.doi.org/10.1021/jm900654c] [PMID: 19537763]
[61]
Vanejevs, M.; Jatzke, C.; Renner, S.; Müller, S.; Hechenberger, M.; Bauer, T.; Klochkova, A.; Pyatkin, I.; Kazyulkin, D.; Aksenova, E.; Shulepin, S.; Timonina, O.; Haasis, A.; Gutcaits, A.; Parsons, C.G.; Kauss, V.; Weil, T. Positive and negative modulation of group I metabotropic glutamate receptors. J. Med. Chem., 2008, 51(3), 634-647.
[http://dx.doi.org/10.1021/jm0611298] [PMID: 18173231]
[62]
Micheli, F.; Bertani, B.; Bozzoli, A.; Crippa, L.; Cavanni, P.; Di Fabio, R.; Donati, D.; Marzorati, P.; Merlo, G.; Paio, A.; Perugini, L.; Zarantonello, P. Phenylethynyl-pyrrolo[1,2-a]pyrazine: a new potent and selective tool in the mGluR5 antagonists arena. Bioorg. Med. Chem. Lett., 2008, 18(6), 1804-1809.
[http://dx.doi.org/10.1016/j.bmcl.2008.02.024] [PMID: 18304814]
[63]
Anighoro, A.; Graziani, D.; Bettinelli, I.; Cilia, A.; De Toma, C.; Longhi, M.; Mangiarotti, F.; Menegon, S.; Pirona, L.; Poggesi, E.; Riva, C.; Rastelli, G. Insights into the interaction of negative allosteric modulators with the metabotropic glutamate receptor 5: discovery and computational modeling of a new series of ligands with nanomolar affinity. Bioorg. Med. Chem., 2015, 23(13), 3040-3058.
[http://dx.doi.org/10.1016/j.bmc.2015.05.008] [PMID: 26014480]
[64]
Kubas, H.; Meyer, U.; Hechenberger, M.; Klein, K-U.; Plitt, P.; Zemribo, R.; Spexgoor, H.W.; van Assema, S.G.A.; Abel, U. Scaffold hopping approach towards various AFQ-056 analogs as potent metabotropic glutamate receptor 5 negative allosteric modulators. Bioorg. Med. Chem. Lett., 2013, 23(23), 6370-6376.
[http://dx.doi.org/10.1016/j.bmcl.2013.09.059] [PMID: 24125886]
[65]
Waung, M.W.; Akerman, S.; Wakefield, M.; Keywood, C.; Goadsby, P.J. Metabotropic glutamate receptor 5: A target for migraine therapy. Ann. Clin. Transl. Neurol., 2016, 3(8), 560-571.
[http://dx.doi.org/10.1002/acn3.302] [PMID: 27606340]
[66]
Brown, A.K.; Kimura, Y.; Zoghbi, S.S.; Siméon, F.G.; Liow, J-S.; Kreisl, W.C.; Taku, A.; Fujita, M.; Pike, V.W.; Innis, R.B. Metabotropic glutamate subtype 5 receptors are quantified in the human brain with a novel radioligand for PET. J. Nucl. Med., 2008, 49(12), 2042-2048.
[http://dx.doi.org/10.2967/jnumed.108.056291] [PMID: 19038998]
[67]
Malherbe, P.; Kratochwil, N.; Mühlemann, A.; Zenner, M-T.; Fischer, C.; Stahl, M.; Gerber, P.R.; Jaeschke, G.; Porter, R.H.P. Comparison of the binding pockets of two chemically unrelated allosteric antagonists of the mGlu5 receptor and identification of crucial residues involved in the inverse agonism of MPEP. J. Neurochem., 2006, 98(2), 601-615.
[http://dx.doi.org/10.1111/j.1471-4159.2006.03886.x] [PMID: 16805850]
[68]
Porter, R.H.P.; Jaeschke, G.; Spooren, W.; Ballard, T.M.; Büttelmann, B.; Kolczewski, S.; Peters, J-U.; Prinssen, E.; Wichmann, J.; Vieira, E.; Mühlemann, A.; Gatti, S.; Mutel, V.; Malherbe, P.; Johnson, E.C. Fenobam: a clinically validated nonbenzodiazepine anxiolytic is a potent, selective, and noncompetitive mGlu5 receptor antagonist with inverse agonist activity. J. Pharmacol. Exp. Ther., 2005, 315(2), 711-721.
[http://dx.doi.org/10.1124/jpet.105.089839] [PMID: 16040814]
[69]
Jaeschke, G.; Porter, R.; Büttelmann, B.; Ceccarelli, S.M.; Guba, W.; Kuhn, B.; Kolczewski, S.; Huwyler, J.; Mutel, V.; Peters, J-U.; Ballard, T.; Prinssen, E.; Vieira, E.; Wichmann, J.; Spooren, W. Synthesis and biological evaluation of fenobam analogs as mGlu5 receptor antagonists. Bioorg. Med. Chem. Lett., 2007, 17(5), 1307-1311.
[http://dx.doi.org/10.1016/j.bmcl.2006.12.033] [PMID: 17196387]
[70]
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.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00892] [PMID: 26225459]
[71]
HTL14242 in phase 1 clinical trial. (Accessed Apr 6 at:. https://soseiheptares.com/our-pipeline/rd-pipeline/in-house-programs.html).
[72]
Roppe, J.; Smith, N.D.; Huang, D.; Tehrani, L.; Wang, B.; Anderson, J.; Brodkin, J.; Chung, J.; Jiang, X.; King, C.; Munoz, B.; Varney, M.A.; Prasit, P.; Cosford, N.D.P. Discovery of novel heteroarylazoles that are metabotropic glutamate subtype 5 receptor antagonists with anxiolytic activity. J. Med. Chem., 2004, 47(19), 4645-4648.
[http://dx.doi.org/10.1021/jm049828c] [PMID: 15341479]
[73]
Zhang, P.; Zou, M-F.; Rodriguez, A.L.; Conn, P.J.; Newman, A.H. Structure-activity relationships in a novel series of 7-substituted-aryl quinolines and 5-substituted-aryl benzothiazoles at the metabotropic glutamate receptor subtype 5. Bioorg. Med. Chem., 2010, 18(9), 3026-3035.
[http://dx.doi.org/10.1016/j.bmc.2010.03.053] [PMID: 20382541]
[74]
Rodriguez, A.L.; Grier, M.D.; Jones, C.K.; Herman, E.J.; Kane, A.S.; Smith, R.L.; Williams, R.; Zhou, Y.; Marlo, J.E.; Days, E.L.; Blatt, T.N.; Jadhav, S.; Menon, U.N.; Vinson, P.N.; Rook, J.M.; Stauffer, S.R.; Niswender, C.M.; Lindsley, C.W.; Weaver, C.D.; Conn, P.J. Discovery of novel allosteric modulators of metabotropic glutamate receptor subtype 5 reveals chemical and functional diversity and in vivo activity in rat behavioral models of anxiolytic and antipsychotic activity. Mol. Pharmacol., 2010, 78(6), 1105-1123.
[http://dx.doi.org/10.1124/mol.110.067207] [PMID: 20923853]
[75]
Bonnefous, C.; Vernier, J-M.; Hutchinson, J.H.; Chung, J.; Reyes-Manalo, G.; Kamenecka, T. Dipyridyl amides: Potent metabotropic glutamate subtype 5 (mGlu5) receptor antagonists. Bioorg. Med. Chem. Lett., 2005, 15(4), 1197-1200.
[http://dx.doi.org/10.1016/j.bmcl.2004.11.078] [PMID: 15686941]
[76]
Wang, B.; Vernier, J-M.; Rao, S.; Chung, J.; Anderson, J.J.; Brodkin, J.D.; Jiang, X.; Gardner, M.F.; Yang, X.; Munoz, B. Discovery of novel modulators of metabotropic glutamate receptor subtype-5. Bioorg. Med. Chem., 2004, 12(1), 17-21.
[http://dx.doi.org/10.1016/j.bmc.2003.10.021] [PMID: 14697765]
[77]
Rodriguez, A.L.; Williams, R.; Zhou, Y.; Lindsley, S.R.; Le, U.; Grier, M.D.; Weaver, C.D.; Conn, P.J.; Lindsley, C.W. Discovery and SAR of novel mGluR5 non-competitive antagonists not based on an MPEP chemotype. Bioorg. Med. Chem. Lett., 2009, 19(12), 3209-3213.
[http://dx.doi.org/10.1016/j.bmcl.2009.04.110] [PMID: 19443219]
[78]
O’Brien, J.A.; Lemaire, W.; Chen, T-B.; Chang, R.S.L.; Jacobson, M.A.; Ha, S.N.; Lindsley, C.W.; Schaffhauser, H.J.; Sur, C.; Pettibone, D.J.; Conn, P.J.; Williams, D.L., Jr; Menon, U.N.; Vinson, P.N.; Rook, J.M.; Stauffer, S.R.; Niswender, C.M.; Lindsley, C.W.; Weaver, C.D.; Conn, P.J. A family of highly selective allosteric modulators of the metabotropic glutamate receptor subtype 5. Mol. Pharmacol., 2003, 64(3), 731-740.
[http://dx.doi.org/10.1124/mol.64.3.731] [PMID: 12920211]
[79]
Kubas, H.; Meyer, U.; Krueger, B.; Hechenberger, M.; Vanejevs, M.; Zemribo, R.; Kauss, V.; Ambartsumova, R.; Pyatkin, I.; Polosukhin, A.I.; Abel, U. Discovery, synthesis, and structure-activity relationships of 2-aminoquinazoline derivatives as a novel class of metabotropic glutamate receptor 5 negative allosteric modulators. Bioorg. Med. Chem. Lett., 2013, 23(16), 4493-4500.
[http://dx.doi.org/10.1016/j.bmcl.2013.06.049] [PMID: 23856046]
[80]
Fu, T.; Zheng, G.; Tu, G.; Yang, F.; Chen, Y.; Yao, X.; Li, X.; Xue, W.; Zhu, F. Exploring the binding mechanism of metabotropic glutamate receptor 5 negative allosteric modulators in clinical trials by molecular dynamics simulations. ACS Chem. Neurosci., 2018, 9(6), 1492-1502.
[http://dx.doi.org/10.1021/acschemneuro.8b00059] [PMID: 29522307]
[81]
Vranesic, I.; Ofner, S.; Flor, P.J.; Bilbe, G.; Bouhelal, R.; Enz, A.; Desrayaud, S.; McAllister, K.; Kuhn, R.; Gasparini, F. AFQ056/mavoglurant, a novel clinically effective mGluR5 antagonist: identification, SAR and pharmacological characterization. Bioorg. Med. Chem., 2014, 22(21), 5790-5803.
[http://dx.doi.org/10.1016/j.bmc.2014.09.033] [PMID: 25316499]
[82]
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.
[http://dx.doi.org/10.1007/s12325-016-0468-5] [PMID: 28044255]
[83]
Rodriguez, A.L.; Williams, R. Recent progress in the development of allosteric modulators of mGluR5. Curr. Opin. Drug Discov. Devel., 2007, 10(6), 715-722.
[PMID: 17987523]
[84]
Lindsley, C.W.; Emmitte, K.A. Recent progress in the discovery and development of negative allosteric modulators of mGluR5. Curr. Opin. Drug Discov. Devel., 2009, 12(4), 446-457.
[PMID: 19562641]
[85]
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.
[http://dx.doi.org/10.1038/nature13396] [PMID: 25042998]
[86]
Marek, G.J.; Behl, B.; Bespalov, A.Y.; Gross, G.; Lee, Y.; Schoemaker, H. Glutamatergic (N-methyl-D-aspartate receptor) hypofrontality in schizophrenia: Too little juice or a miswired brain? Mol. Pharmacol., 2010, 77(3), 317-326.
[http://dx.doi.org/10.1124/mol.109.059865] [PMID: 19933774]
[87]
Packiarajan, M.; Grenon, M.; Zorn, S.; Hopper, A.T.; White, A.D.; Chandrasena, G.; Pu, X.; Brodbeck, R.M.; Robichaud, A.J. Fused thiazolyl alkynes as potent mGlu5 receptor positive allosteric modulators. Bioorg. Med. Chem. Lett., 2013, 23(14), 4037-4043.
[http://dx.doi.org/10.1016/j.bmcl.2013.05.070] [PMID: 23770058]
[88]
Williams, R.; Manka, J.T.; Rodriguez, A.L.; Vinson, P.N.; Niswender, C.M.; Weaver, C.D.; Jones, C.K.; Conn, P.J.; Lindsley, C.W.; Stauffer, S.R. Synthesis and SAR of centrally active mGlu5 positive allosteric modulators based on an aryl acetylenic bicyclic lactam scaffold. Bioorg. Med. Chem. Lett., 2011, 21(5), 1350-1353.
[http://dx.doi.org/10.1016/j.bmcl.2011.01.044] [PMID: 21315585]
[89]
Bartolomé-Nebreda, J.M.; Conde-Ceide, S.; Delgado, F.; Iturrino, L.; Pastor, J.; Pena, M.Á.; Trabanco, A.A.; Tresadern, G.; Wassvik, C.M.; Stauffer, S.R.; Jadhav, S.; Gogi, K.; Vinson, P.N.; Noetzel, M.J.; Days, E.; Weaver, C.D.; Lindsley, C.W.; Niswender, C.M.; Jones, C.K.; Conn, P.J.; Rombouts, F.; Lavreysen, H.; Macdonald, G.J.; Mackie, C.; Steckler, T. Dihydrothiazolopyridone derivatives as a novel family of positive allosteric modulators of the metabotropic glutamate 5 (mGlu5) receptor. J. Med. Chem., 2013, 56(18), 7243-7259.
[http://dx.doi.org/10.1021/jm400650w] [PMID: 23947773]
[90]
Varnes, J.G.; Marcus, A.P.; Mauger, R.C.; Throner, S.R.; Hoesch, V.; King, M.M.; Wang, X.; Sygowski, L.A.; Spear, N.; Gadient, R.; Brown, D.G.; Campbell, J.B. Discovery of novel positive allosteric modulators of the metabotropic glutamate receptor 5 (mGlu5). Bioorg. Med. Chem. Lett., 2011, 21(5), 1402-1406.
[http://dx.doi.org/10.1016/j.bmcl.2011.01.027] [PMID: 21295468]
[91]
Malosh, C.; Turlington, M.; Bridges, T.M.; Rook, J.M.; Noetzel, M.J.; Vinson, P.N.; Steckler, T.; Lavreysen, H.; Mackie, C.; Bartolomé-Nebreda, J.M.; Conde-Ceide, S.; Martínez-Viturro, C.M.; Piedrafita, M.; Sánchez-Casado, M.R.; Macdonald, G.J.; Daniels, J.S.; Jones, C.K.; Niswender, C.M.; Conn, P.J.; Lindsley, C.W.; Stauffer, S.R. Acyl dihydropyrazolo[1,5-a]pyrimidinones as metabotropic glutamate receptor 5 positive allosteric modulators. Bioorg. Med. Chem. Lett., 2015, 25(22), 5115-5120.
[http://dx.doi.org/10.1016/j.bmcl.2015.10.009] [PMID: 26475522]
[92]
Koehl, A.; Hu, H.; Feng, D.; Sun, B.; Zhang, Y.; Robertson, M.J.; Chu, M.; Kobilka, T.S.; Laeremans, T.; Steyaert, J.; Tarrasch, J.; Dutta, S.; Fonseca, R.; Weis, W.I.; Mathiesen, J.M.; Skiniotis, G.; Kobilka, B.K. Structural insights into the activation of metabotropic glutamate receptors. Nature, 2019, 566(7742), 79-84.
[http://dx.doi.org/10.1038/s41586-019-0881-4] [PMID: 30675062]
[93]
Cong, X.; Chéron, J-B.; Golebiowski, J.; Antonczak, S.; Fiorucci, S. Allosteric modulation mechanism of the MGluR 5 transmembrane domain. J. Chem. Inf. Model., 2019, 59(6), 2871-2878.
[http://dx.doi.org/10.1021/acs.jcim.9b00045] [PMID: 31025859]
[94]
Pérez-Benito, L.; Doornbos, M.L.J.; Cordomí, A.; Peeters, L.; Lavreysen, H.; Pardo, L.; Tresadern, G. Molecular switches of allosteric modulation of the metabotropic glutamate 2 receptor. Structure, 2017, 25(7), 1153-1162.
[http://dx.doi.org/10.1016/j.str.2017.05.021] [PMID: 28648611]
[95]
Dalton, J.A.R.; Pin, J.P.; Giraldo, J. Analysis of positive and negative allosteric modulation in metabotropic glutamate receptors 4 and 5 with a dual ligand. Sci. Rep., 2017, 7(1), 4944.
[http://dx.doi.org/10.1038/s41598-017-05095-5] [PMID: 28694498]
[96]
Llinas Del Torrent, C.; Casajuana-Martin, N.; Pardo, L.; Tresadern, G.; Pérez-Benito, L. Mechanisms underlying allosteric molecular switches of metabotropic glutamate receptor 5. J. Chem. Inf. Model., 2019, 59(5), 2456-2466.
[http://dx.doi.org/10.1021/acs.jcim.8b00924] [PMID: 30811196]
[97]
Jójárt, B.; Orgován, Z.; Márki, Á.; Pándy-Szekeres, G.; Ferenczy, G.G.; Keserű, G.M. Allosteric activation of metabotropic glutamate receptor 5. J. Biomol. Struct. Dyn., 2019, 1-9.
[http://dx.doi.org/10.1080/07391102.2019.1638302] [PMID: 31258022]
[98]
Cartmell, J.; Schoepp, D.D. Regulation of neurotransmitter release by metabotropic glutamate receptors. J. Neurochem., 2000, 75(3), 889-907.
[http://dx.doi.org/10.1046/j.1471-4159.2000.0750889.x] [PMID: 10936169]
[99]
Petralia, R.S.; Wang, Y-X.; Niedzielski, A.S.; Wenthold, R.J. The metabotropic glutamate receptors, mGluR2 and mGluR3, show unique postsynaptic, presynaptic and glial localizations. Neuroscience, 1996, 71(4), 949-976.
[http://dx.doi.org/10.1016/0306-4522(95)00533-1] [PMID: 8684625]
[100]
Linden, A-M.; Schoepp, D.D. Metabotropic glutamate receptor targets for neuropsychiatric disorders. Drug Discov. Today Ther. Strateg., 2006, 3, 507-517.
[http://dx.doi.org/10.1016/j.ddstr.2006.10.018]
[101]
Woolley, M.L.; Pemberton, D.J.; Bate, S.; Corti, C.; Jones, D.N.C. The mGlu2 but not the mGlu3 receptor mediates the actions of the mGluR2/3 agonist, LY379268, in mouse models predictive of antipsychotic activity. Psychopharmacology (Berl.), 2008, 196(3), 431-440.
[http://dx.doi.org/10.1007/s00213-007-0974-x] [PMID: 18057917]
[102]
Fell, M.J.; Svensson, K.A.; Johnson, B.G.; Schoepp, D.D. Evidence for the role of metabotropic glutamate (mGlu)2 not mGlu3 receptors in the preclinical antipsychotic pharmacology of the mGlu2/3 receptor agonist (-)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo [3.1.0]hexane-4,6-dicarboxylic acid (LY404039). J. Pharmacol. Exp. Ther., 2008, 326(1), 209-217.
[http://dx.doi.org/10.1124/jpet.108.136861] [PMID: 18424625]
[103]
Jin, C.; Ma, S. Recent advances in the medicinal chemistry of group II and group III mGlu receptors. MedChemComm, 2017, 8(3), 501-515.
[http://dx.doi.org/10.1039/C6MD00612D] [PMID: 30108768]
[104]
Cid, J.M.; Duvey, G.; Tresadern, G.; Nhem, V.; Furnari, R.; Cluzeau, P.; Vega, J.A.; de Lucas, A.I.; Matesanz, E.; Alonso, J.M.; Linares, M.L.; Andrés, J.I.; Poli, S.M.; Lutjens, R.; Himogai, H.; Rocher, J-P.; Macdonald, G.J.; Oehlrich, D.; Lavreysen, H.; Ahnaou, A.; Drinkenburg, W.; Mackie, C.; Trabanco, A.A. Discovery of 1,4-disubstituted 3-cyano-2-pyridones: a new class of positive allosteric modulators of the metabotropic glutamate 2 receptor. J. Med. Chem., 2012, 55(5), 2388-2405.
[http://dx.doi.org/10.1021/jm2016864] [PMID: 22364337]
[105]
Cid, J.M.; Tresadern, G.; Duvey, G.; Lütjens, R.; Finn, T.; Rocher, J-P.; Poli, S.; Vega, J.A.; de Lucas, A.I.; Matesanz, E.; Linares, M.L.; Andrés, J.I.; Alcazar, J.; Alonso, J.M.; Macdonald, G.J.; Oehlrich, D.; Lavreysen, H.; Ahnaou, A.; Drinkenburg, W.; Mackie, C.; Pype, S.; Gallacher, D.; Trabanco, A.A. Discovery of 1-butyl-3-chloro-4-(4-phenyl-1-piperidinyl)-(1H)-pyridone (JNJ-40411813): a novel positive allosteric modulator of the metabotropic glutamate 2 receptor. J. Med. Chem., 2014, 57(15), 6495-6512.
[http://dx.doi.org/10.1021/jm500496m] [PMID: 25032784]
[106]
Walker, A.G.; Conn, P.J.; Group, I.; Group, I.I. Group I and group II metabotropic glutamate receptor allosteric modulators as novel potential antipsychotics. Curr. Opin. Pharmacol., 2015, 20, 40-45.
[http://dx.doi.org/10.1016/j.coph.2014.11.003] [PMID: 25462291]
[107]
Lavreysen, H.; Ahnaou, A.; Drinkenburg, W.; Langlois, X.; Mackie, C.; Pype, S.; Lütjens, R.; Le Poul, E.; Trabanco, A.A.; Nuñez, J.M.C. Pharmacological and pharmacokinetic properties of JNJ-40411813, a positive allosteric modulator of the mGlu2 receptor. Pharmacol. Res. Perspect., 2015, 3(1)e00096
[http://dx.doi.org/10.1002/prp2.96] [PMID: 25692015]
[108]
Lavreysen, H.; Langlois, X.; Donck, L.V.; Nuñez, J.M.C.; Pype, S.; Lütjens, R.; Megens, A. Preclinical evaluation of the antipsychotic potential of the mGlu2-positive allosteric modulator JNJ-40411813. Pharmacol. Res. Perspect., 2015, 3(2)e00097
[http://dx.doi.org/10.1002/prp2.97] [PMID: 25692027]
[109]
Layton, M.E.; Reif, A.J.; Hartingh, T.J.; Rodzinak, K.; Dudkin, V.; Wang, C.; Arrington, K.; Kelly, M.J., III; Garbaccio, R.M.; O’Brien, J.A.; Magliaro, B.C.; Uslaner, J.M.; Huszar, S.L.; Fillgrove, K.L.; Tang, C.; Kuo, Y.; Jacobson, M.A. Discovery of 5-aryl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-ones as positive allosteric modulators of metabotropic glutamate subtype-2 (mGlu2) receptors with efficacy in a preclinical model of psychosis. Bioorg. Med. Chem. Lett., 2016, 26(4), 1260-1264.
[http://dx.doi.org/10.1016/j.bmcl.2016.01.021] [PMID: 26810316]
[110]
Pero, J.E.; Rossi, M.A.; Kelly, M.J., III; Lehman, H.D.G.F.; Layton, M.E.; Garbaccio, R.M.; O’Brien, J.A.; Magliaro, B.C.; Uslaner, J.M.; Huszar, S.L.; Fillgrove, K.L.; Tang, C.; Kuo, Y.; Joyce, L.A.; Sherer, E.C.; Jacobson, M.A. Optimization of novel aza-benzimidazolone mGluR2 PAMs with respect to LLE and PK properties and mitigation of CYP TDI. ACS Med. Chem. Lett., 2016, 7(3), 312-317.
[http://dx.doi.org/10.1021/acsmedchemlett.5b00459] [PMID: 26985321]
[111]
Szabó, G.; Túrós, G.I.; Kolok, S.; Vastag, M.; Sánta, Z.; Dékány, M.; Lévay, G.I.; Greiner, I.; Natsumi, M.; Tatsuya, W.; Keserű, G.M. Fragment based optimization of metabotropic glutamate receptor 2 (mGluR2) positive allosteric modulators in the absence of structural information. J. Med. Chem., 2019, 62(1), 234-246.
[http://dx.doi.org/10.1021/acs.jmedchem.8b00161] [PMID: 29505715]
[112]
Valenti, O.; Marino, M.J.; Wittmann, M.; Lis, E.; DiLella, A.G.; Kinney, G.G.; Conn, P.J. Group III metabotropic glutamate receptor-mediated modulation of the striatopallidal synapse. J. Neurosci., 2003, 23(18), 7218-7226.
[http://dx.doi.org/10.1523/JNEUROSCI.23-18-07218.2003] [PMID: 12904482]
[113]
Stachowicz, K.; Kłak, K.; Kłodzińska, A.; Chojnacka-Wojcik, E.; Pilc, A. Anxiolytic-like effects of PHCCC, an allosteric modulator of mGlu4 receptors, in rats. Eur. J. Pharmacol., 2004, 498(1-3), 153-156.
[http://dx.doi.org/10.1016/j.ejphar.2004.07.001] [PMID: 15363989]
[114]
Marino, M.J.; Williams, D.L., Jr; O’Brien, J.A.; Valenti, O.; McDonald, T.P.; Clements, M.K.; Wang, R.; DiLella, A.G.; Hess, J.F.; Kinney, G.G.; Conn, P.J.; Conn, P.J. Allosteric modulation of group III metabotropic glutamate receptor 4: a potential approach to Parkinson’s disease treatment. Proc. Natl. Acad. Sci. USA, 2003, 100(23), 13668-13673.
[http://dx.doi.org/10.1073/pnas.1835724100] [PMID: 14593202]
[115]
Mathiesen, J.M.; Svendsen, N.; Bräuner-Osborne, H.; Thomsen, C.; Ramirez, M.T. Positive allosteric modulation of the human metabotropic glutamate receptor 4 (hmGluR4) by SIB-1893 and MPEP. Br. J. Pharmacol., 2003, 138(6), 1026-1030.
[http://dx.doi.org/10.1038/sj.bjp.0705159] [PMID: 12684257]
[116]
Maj, M.; Bruno, V.; Dragic, Z.; Yamamoto, R.; Battaglia, G.; Inderbitzin, W.; Stoehr, N.; Stein, T.; Gasparini, F.; Vranesic, I.; Kuhn, R.; Nicoletti, F.; Flor, P.J. (-)-PHCCC, a positive allosteric modulator of mGluR4: characterization, mechanism of action, and neuroprotection. Neuropharmacology, 2003, 45(7), 895-906.
[http://dx.doi.org/10.1016/S0028-3908(03)00271-5] [PMID: 14573382]
[117]
Beqollari, D.; Kammermeier, P.J. The mGlu(4) receptor allosteric modulator N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide acts as a direct agonist at mGlu(6) receptors. Eur. J. Pharmacol., 2008, 589(1-3), 49-52.
[http://dx.doi.org/10.1016/j.ejphar.2008.06.054] [PMID: 18593581]
[118]
Williams, R.; Zhou, Y.; Niswender, C.M.; Luo, Q.; Conn, P.J.; Lindsley, C.W.; Hopkins, C.R. Re-exploration of the PHCCC Scaffold: Discovery of Improved Positive Allosteric Modulators of mGluR4. ACS Chem. Neurosci., 2010, 1(6), 411-419.
[http://dx.doi.org/10.1021/cn9000318] [PMID: 20582156]
[119]
Williams, R.; Niswender, C.M.; Luo, Q.; Le, U.; Conn, P.J.; Lindsley, C.W. Positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mGluR4). Part II: Challenges in hit-to-lead. Bioorg. Med. Chem. Lett., 2009, 19(3), 962-966.
[http://dx.doi.org/10.1016/j.bmcl.2008.11.104] [PMID: 19097893]
[120]
East, S.P.; Bamford, S.; Dietz, M.G.A.; Eickmeier, C.; Flegg, A.; Ferger, B.; Gemkow, M.J.; Heilker, R.; Hengerer, B.; Kotey, A.; Loke, P.; Schänzle, G.; Schubert, H-D.; Scott, J.; Whittaker, M.; Williams, M.; Zawadzki, P.; Gerlach, K. An orally bioavailable positive allosteric modulator of the mGlu4 receptor with efficacy in an animal model of motor dysfunction. Bioorg. Med. Chem. Lett., 2010, 20(16), 4901-4905.
[http://dx.doi.org/10.1016/j.bmcl.2010.06.078] [PMID: 20638279]
[121]
Engers, D.W.; Niswender, C.M.; Weaver, C.D.; Jadhav, S.; Menon, U.N.; Zamorano, R.; Conn, P.J.; Lindsley, C.W.; Hopkins, C.R. Synthesis and evaluation of a series of heterobiarylamides that are centrally penetrant metabotropic glutamate receptor 4 (mGluR4) positive allosteric modulators (PAMs). J. Med. Chem., 2009, 52(14), 4115-4118.
[http://dx.doi.org/10.1021/jm9005065] [PMID: 19469556]
[122]
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.
[http://dx.doi.org/10.1021/acschemneuro.6b00035] [PMID: 27075300]
[123]
Bolea, C.; Celanire, S. Pyrazole derivatives as modulators of metabotropic glutamate receptors. Patent WO2009010455A2, May 03, 2009.
[124]
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.
[http://dx.doi.org/10.1007/s11481-016-9655-z] [PMID: 26872456]
[125]
Hong, S-P.; Liu, K.G.; Ma, G.; Sabio, M.; Uberti, M.A.; Bacolod, M.D.; Peterson, J.; Zou, Z.Z.; Robichaud, A.J.; Doller, D. Tricyclic thiazolopyrazole derivatives as metabotropic glutamate receptor 4 positive allosteric modulators. J. Med. Chem., 2011, 54(14), 5070-5081.
[http://dx.doi.org/10.1021/jm200290z] [PMID: 21688779]
[126]
Jimenez, H.N.; Liu, K.G.; Hong, S-P.; Reitman, M.S.; Uberti, M.A.; Bacolod, M.D.; Cajina, M.; Nattini, M.; Sabio, M.; Doller, D. 4-(1-Phenyl-1H-pyrazol-4-yl)quinolines as novel, selective and brain penetrant metabotropic glutamate receptor 4 positive allosteric modulators. Bioorg. Med. Chem. Lett., 2012, 22(9), 3235-3239.
[http://dx.doi.org/10.1016/j.bmcl.2012.03.032] [PMID: 22465637]
[127]
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.
[http://dx.doi.org/10.1124/jpet.112.200915] [PMID: 23257312]
[128]
Bian, Y.; Feng, Z.; Yang, P.; Xie, X-Q. Integrated in silico fragment-based drug design: Case study with allosteric modulators on metabotropic glutamate receptor 5. AAPS J., 2017, 19(4), 1235-1248.
[http://dx.doi.org/10.1208/s12248-017-0093-5] [PMID: 28560482]
[129]
Llinas Del Torrent, C.; Pérez-Benito, L.; Tresadern, G. Computational drug design applied to the study of metabotropic glutamate receptors. Molecules, 2019, 24(6), 24.
[http://dx.doi.org/10.3390/molecules24061098] [PMID: 30897742]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 19
ISSUE: 19
Year: 2019
Page: [1768 - 1781]
Pages: 14
DOI: 10.2174/1568026619666190808150039
Price: $58

Article Metrics

PDF: 19
HTML: 2