Molecular insights into metabotropic glutamate receptor allosteric modulations

Molecular Pharmacology

Volumn 88, Issue 1, 2015, Pages 188-202

  Gregory, Karen J ^a   Conn, P Jeffrey ^b  

^a MONASH UNIVERSITY   (Australia)

^b VANDERBILT UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 (3,5 DICHLOROPHENYLCARBAMOYL)CYCLOHEXANECARBOXYLIC ACID; ADX 71743; AMINO ACID; AZ 12216052; LIGAND; METABOTROPIC RECEPTOR; N,N' DIBENZHYDRYLETHYLENEDIAMINE; UNCLASSIFIED DRUG; VU 0155094; VU 0422288; BENZHYDRYL DERIVATIVE; N,N'-DIBENZHYDRYLETHANE-1,2-DIAMINE DIHYDROCHLORIDE;

ALLOSTERISM; BINDING SITE; CRYSTAL STRUCTURE; DRUG TARGETING; INVERSE AGONISM; LIGAND BINDING; PHARMACOLOGY; PRIORITY JOURNAL; PROTEIN PROTEIN INTERACTION; SHORT SURVEY; STRUCTURE ACTIVITY RELATION; X RAY CRYSTALLOGRAPHY; CENTRAL NERVOUS SYSTEM; CHEMISTRY; DRUG DESIGN; HUMAN; METABOLISM; MOLECULARLY TARGETED THERAPY; PATHOLOGY; PROTEIN CONFORMATION;

ALLOSTERIC SITE; BENZHYDRYL COMPOUNDS; CENTRAL NERVOUS SYSTEM; DRUG DESIGN; HUMANS; MOLECULAR TARGETED THERAPY; PROTEIN CONFORMATION; RECEPTORS, METABOTROPIC GLUTAMATE;

EID: 84939627772     PISSN: 0026895X     EISSN: 15210111     Source Type: Journal    
DOI: 10.1124/mol.114.097220     Document Type: Short Survey

References (150)

1. Ametamey SM, Treyer V, Streffer J, Wyss MT, Schmidt M, Blagoev M, Hintermann S, Auberson Y, Gasparini F, and Fischer UC et al. (2007) Human PET studies of metabotropic glutamate receptor subtype 5 with 11C-ABP688. J Nucl Med 48:247-252.
2. Anderson JJ, Bradbury MJ, Giracello DR, Chapman DF, Holtz G, Roppe J, King C, Cosford ND, and Varney MA (2003) In vivo receptor occupancy of mGlu5 receptor antagonists using the novel radioligand [3H]3-methoxy-5-(pyridin-2-ylethynyl)pyridine). Eur J Pharmacol 473:35-40.
3. Anderson JJ, Rao SP, Rowe B, Giracello DR, Holtz G, Chapman DF, Tehrani L, Bradbury MJ, Cosford ND, and Varney MA (2002) [3H]Methoxymethyl-3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine binding to metabotropic glutamate receptor subtype 5 in rodent brain: in vitro and in vivo characterization. J Pharmacol Exp Ther 303:1044-1051.
4. Annoura H, Fukunaga A, Uesugi M, Tatsuoka T, and Horikawa Y (1996) A novel class of antagonists for metabotropic glutamate receptors, 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylates. Bioorg Med Chem Lett 6:763-766.
5. Anwyl R (1999) Metabotropic glutamate receptors: electrophysiological properties and role in plasticity. Brain Res Brain Res Rev 29:83-120.
6. Ayala JE, Chen Y, Banko JL, Sheffler DJ, Williams R, Telk AN, Watson NL, Xiang Z, Zhang Y, and Jones PJ et al. (2009) mGluR5 positive allosteric modulators facilitate both hippocampal LTP and LTD and enhance spatial learning. Neuropsychopharmacology 34:2057-2071.
7. Ayala JE, Niswender CM, Luo Q, Banko JL, and Conn PJ (2008) Group III mGluR regulation of synaptic transmission at the SC-CA1 synapse is developmentally regulated. Neuropharmacology 54:804-814.
8. Ballesteros J and Weinstein H (1995) Integrated methods for the construction of three dimensional models and computational probing of structure-function relations in G-protein coupled receptors. Methods Neurosci 25:366-428.
9. Baumann CA, Mu L, Wertli N, Krämer SD, Honer M, Schubiger PA, and Ametamey SM (2010) Syntheses and pharmacological characterization of novel thiazole derivatives as potential mGluR5 PET ligands. Bioorg Med Chem 18:6044-6054.
10. Becker JA, Clesse D, Spiegelhalter C, Schwab Y, Le Merrer J, and Kieffer BL (2014) Autistic-like syndrome in mu opioid receptor null mice is relieved by facilitated mGluR4 activity. Neuropsychopharmacology 39:2049-2060.
11. Bellone C, Lüscher C, and Mameli M (2008) Mechanisms of synaptic depression triggered by metabotropic glutamate receptors. Cell Mol Life Sci 65:2913-2923.
12. Belozertseva IV, Kos T, Popik P, Danysz W, and Bespalov AY (2007) Antidepressant-like effects of mGluR1 and mGluR5 antagonists in the rat forced swim and the mouse tail suspension tests. Eur Neuropsychopharmacol 17:172-179.
13. Bennett CE, Burnett DA, Greenlee WJ, Knutson CE, Korakas P, Li C, Tulshian D, Wu WL, Bertorelli R, and Fredduzzi S et al. (2012) Fused tricyclic mGluR1 antagonists for the treatment of neuropathic pain. Bioorg Med Chem Lett 22:1575-1578.
14. Beqollari D and Kammermeier PJ (2008) 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 589:49-52.
15. Berry-Kravis E, Hessl D, Coffey S, Hervey C, Schneider A, Yuhas J, Hutchison J, Snape M, Tranfaglia M, and Nguyen DV et al. (2009) A pilot open label, single dose trial of fenobam in adults with fragile X syndrome. J Med Genet 46:266-271.
16. Bradley SJ, Langmead CJ, Watson JM, and Challiss RA (2011) Quantitative analysis reveals multiple mechanisms of allosteric modulation of the mGlu5 receptor in rat astroglia. Mol Pharmacol 79:874-885.
17. Bräuner-Osborne H, Jensen AA, and Krogsgaard-Larsen P (1999) Interaction of CPCCOEt with a chimeric mGlu1b and calcium sensing receptor. Neuroreport 10:3923-3925.
18. Cabello N, Gandía J, Bertarelli DC, Watanabe M, Lluís C, Franco R, Ferré S, Luján R, and Ciruela F (2009) Metabotropic glutamate type 5, dopamine D2 and adenosine A2a receptors form higher-order oligomers in living cells. J Neurochem 109: 1497-1507.
19. Campo B, Kalinichev M, Lambeng N, El Yacoubi M, Royer-Urios I, Schneider M, Legrand C, Parron D, Girard F, and Bessif A et al. (2011) Characterization of an mGluR2/3 negative allosteric modulator in rodent models of depression. J Neurogenet 25:152-166.
20. Carroll FY, Stolle A, Beart PM, Voerste A, Brabet I, Mauler F, Joly C, Antonicek H, Bockaert J, and Müller T et al. (2001) BAY36-7620: a potent non-competitive mGlu1 receptor antagonist with inverse agonist activity. Mol Pharmacol 59:965-973.
21. Chaki S, Ago Y, Palucha-Paniewiera A, Matrisciano F, and Pilc A (2013) mGlu2/3 and mGlu5 receptors: potential targets for novel antidepressants. Neuropharmacology 66:40-52.
22. Chen Y, Goudet C, Pin JP, and Conn PJ (2008) N-4-Chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl-2-hydroxybenzamide(CPPHA) acts through a novel site as a positive allosteric modulator of group 1 metabotropic glutamate receptors. Mol Pharmacol 73:909-918.
23. Chen Y, Nong Y, Goudet C, Hemstapat K, de Paulis T, Pin JP, and Conn PJ (2007) Interaction of novel positive allosteric modulators of metabotropic glutamate receptor 5 with the negative allosteric antagonist site is required for potentiation of receptor responses. Mol Pharmacol 71:1389-1398.
24. Christopoulos A (2014) Advances in G protein-coupled receptor allostery: from function to structure. Mol Pharmacol 86:463-478.
25. Christopoulos A, Changeux JP, Catterall WA, Fabbro D, Burris TP, Cidlowski JA, Olsen RW, Peters JA, Neubig RR, and Pin JP et al. (2014) International union of basic and clinical pharmacology. XC. multisite pharmacology: recommendations for the nomenclature of receptor allosterism and allosteric ligands. Pharmacol Rev 66:918-947.
26. Conn PJ, Lindsley CW, Meiler J, and Niswender CM (2014) Opportunities and challenges in the discovery of allosteric modulators of GPCRs for treating CNS disorders. Nat Rev Drug Discov 13:692-708.
27. Conn PJ and Pin JP (1997) Pharmacology and functions of metabotropic glutamate receptors. Annu Rev Pharmacol Toxicol 37:205-237.
28. Cosford ND, Roppe J, Tehrani L, Schweiger EJ, Seiders TJ, Chaudary A, Rao S, and Varney MA (2003b) [3H]-methoxymethyl-MTEP and [3H]-methoxy-PEPy: potent and selective radioligands for the metabotropic glutamate subtype 5 (mGlu5) receptor. Bioorg Med Chem Lett 13:351-354.
29. Coutinho V and Knöpfel T (2002) Metabotropic glutamate receptors: electrical and chemical signaling properties. Neuroscientist 8:551-561.
30. Doré AS, Okrasa K, Patel JC, Serrano-Vega M, Bennett K, Cooke RM, Errey JC, Jazayeri A, Khan S, and Tehan B et al. (2014) Structure of class C GPCR metabotropic glutamate receptor 5 transmembrane domain. Nature 511:557-562.
31. Doria JG, Silva FR, de Souza JM, Vieira LB, Carvalho TG, Reis HJ, Pereira GS, Dobransky T, and Ribeiro FM (2013) Metabotropic glutamate receptor 5 positive allosteric modulators are neuroprotective in a mouse model of Huntington's disease. Br J Pharmacol 169:909-921.
32. Doumazane E, Scholler P, Zwier JM, Trinquet E, Rondard P, and Pin JP (2011) A new approach to analyze cell surface protein complexes reveals specific heterodimeric metabotropic glutamate receptors. FASEB J 25:66-77.
33. Dunayevich E, Erickson J, Levine L, Landbloom R, Schoepp DD, and Tollefson GD (2008) Efficacy and tolerability of an mGlu2/3 agonist in the treatment of generalized anxiety disorder. Neuropsychopharmacology 33:1603-1610.
34. Duvoisin RM, Pfankuch T, Wilson JM, Grabell J, Chhajlani V, Brown DG, Johnson E, and Raber J (2010) Acute pharmacological modulation of mGluR8 reduces measures of anxiety. Behav Brain Res 212:168-173.
35. El Moustaine D, Granier S, Doumazane E, Scholler P, Rahmeh R, Bron P, Mouillac B, Banères JL, Rondard P, and Pin JP (2012) Distinct roles of metabotropic glutamate receptor dimerization in agonist activation and G-protein coupling. Proc Natl Acad Sci USA 109:16342-16347.
36. Emery AC, Diraddo JO, Miller E, Hathaway HA, Pshenichkin S, Takoudjou GR, Grajkowska E, Yasuda RP, Wolfe BB, and Wroblewski J (2012) Ligand Bias at Metabotropic Glutamate 1a Receptor: Molecular Determinants that Distinguish beta-arrestin from G Protein Mediated Signaling. Mol Pharmacol 82:95-105.
37. Fell MJ, Witkin JM, Falcone JF, Katner JS, Perry KW, Hart J, Rorick-Kehn L, Overshiner CD, Rasmussen K, and Chaney SF et al. (2011) N-(4-((2-(trifluoromethyl)-3-hydroxy-4-(isobutyryl)phenoxy)methyl)benzyl)-1-methyl-1Himidazole-4-carboxamide (THIIC), a novel metabotropic glutamate 2 potentiator with potential anxiolytic/antidepressant properties: in vivo profiling suggests a link between behavioral and central nervous system neurochemical changes. J Pharmacol Exp Ther 336:165-177.
38. Felts AS, Lindsley SR, Lamb JP, Rodriguez AL, Menon UN, Jadhav S, Jones CK, Conn PJ, Lindsley CW, and Emmitte KA (2010) 3-Cyano-5-fluoro-Narylbenzamides as negative allosteric modulators of mGlu(5): Identification of easily prepared tool compounds with CNS exposure in rats. Bioorg Med Chem Lett 20:4390-4394.
39. Fukuda J, Suzuki G, Kimura T, Nagatomi Y, Ito S, Kawamoto H, Ozaki S, and Ohta H (2009) Identification of a novel transmembrane domain involved in the negative modulation of mGluR1 using a newly discovered allosteric mGluR1 antagonist, 3-cyclohexyl-5-fluoro-6-methyl-7-(2-morpholin-4-ylethoxy)-4H-chromen-4-one. Neuropharmacology 57:438-445.
40. Galici R, Jones CK, Hemstapat K, Nong Y, Echemendia NG, Williams LC, de Paulis T, and Conn PJ (2006) Biphenyl-indanone A, a positive allosteric modulator of the metabotropic glutamate receptor subtype 2, has antipsychotic- and anxiolytic-like effects in mice. J Pharmacol Exp Ther 318:173-185.
41. Gama L, Wilt SG, and Breitwieser GE (2001) Heterodimerization of calcium sensing receptors with metabotropic glutamate receptors in neurons. J Biol Chem 276:39053-39059.
42. Gasparini F, Andres H, Flor PJ, Heinrich M, Inderbitzin W, Lingenhöhl K, Müller H, Munk VC, Omilusik K, and Stierlin C et al. (2002) [(3)H]-M-MPEP, a potent, subtype-selective radioligand for the metabotropic glutamate receptor subtype 5. Bioorg Med Chem Lett 12:407-409.
43. Gasparini F, Floersheim P, Flor PJ, Heinrich M, Inderbitzin W, Ott D, Pagano A, Stierlin C, Stoehr N, and Vranesic I et al. (2001) Discovery and characterization of non-competitive antagonists of group I metabotropic glutamate receptors. Farmaco 56:95-99.
44. Gasparini F, Lingenhohl K, Stoehr N, Flor PJ, Heinrich M, Vranesic I, Biollaz M, Allgeier H, Heckendorn R, Urwyler S et al. (1999) 2-Methyl-6-(phenylethynyl)-pyridine (MPEP), a potent, selective and systemically active mGlu5 receptor antagonist. Neuropharmacology 38:1493-503.
45. González-Maeso J, Ang RL, Yuen T, Chan P, Weisstaub NV, López-Gime'nez JF, Zhou M, Okawa Y, Callado LF, and Milligan G et al. (2008) Identification of a serotonin/glutamate receptor complex implicated in psychosis. Nature 452:93-97.
46. Goudet C, Gaven F, Kniazeff J, Vol C, Liu J, Cohen-Gonsaud M, Acher F, Prézeau L, and Pin JP (2004) Heptahelical domain of metabotropic glutamate receptor 5 behaves like rhodopsin-like receptors. Proc Natl Acad Sci USA 101:378-383.
47. Goudet C, Kniazeff J, Hlavackova V, Malhaire F, Maurel D, Acher F, Blahos J, Prézeau L, and Pin JP (2005) Asymmetric functioning of dimeric metabotropic glutamate receptors disclosed by positive allosteric modulators. J Biol Chem 280:24380-24385.
48. Gregory KJ, Herman EJ, Ramsey AJ, Hammond AS, Byun NE, Stauffer SR, Manka JT, Jadhav S, Bridges TM, and Weaver CD et al. (2013a) N-aryl piperazine metabotropic glutamate receptor 5 positive allosteric modulators possess efficacy in preclinical models of NMDA hypofunction and cognitive enhancement. J Pharmacol Exp Ther 347:438-457.
49. Gregory KJ, Nguyen ED, Malosh C, Mendenhall JL, Zic JZ, Bates BS, Noetzel MJ, Squire EF, Turner EM, and Rook JM et al. (2014) Identification of specific ligand-receptor interactions that govern binding and cooperativity of diverse modulators to a common metabotropic glutamate receptor 5 allosteric site. ACS Chem Neurosci 5:282-295.
50. Gregory KJ, Nguyen ED, Reiff SD, Squire EF, Stauffer SR, Lindsley CW, Meiler J, and Conn PJ (2013b) Probing the metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulator (PAM) binding pocket: discovery of point mutations that engender a "molecular switch" in PAM pharmacology. Mol Pharmacol 83:991-1006.
51. Gregory KJ, Noetzel MJ, Rook JM, Vinson PN, Stauffer SR, Rodriguez AL, Emmitte KA, Zhou Y, Chun AC, and Felts AS et al. (2012) Investigating metabotropic glutamate receptor 5 allosteric modulator cooperativity, affinity, and agonism: enriching structure-function studies and structure-activity relationships. Mol Pharmacol 82:860-875.
52. Gubellini P, Saulle E, Centonze D, Bonsi P, Pisani A, Bernardi G, Conquet F, and Calabresi P (2001) Selective involvement of mGlu1 receptors in corticostriatal LTD. Neuropharmacology 40:839-846.
53. Hammer R, Berrie CP, Birdsall NJ, Burgen AS, and Hulme EC (1980) Pirenzepine distinguishes between different subclasses of muscarinic receptors. Nature 283:90-92.
54. Hammond AS, Rodriguez AL, Townsend SD, Niswender CM, Gregory KJ, Lindsley CW, and Conn PJ (2010) Discovery of a Novel Chemical Class of mGlu(5) Allosteric Ligands with Distinct Modes of Pharmacology. ACS Chem Neurosci 1:702-716.
55. Hemstapat K, Da Costa H, Nong Y, Brady AE, Luo Q, Niswender CM, Tamagnan GD, and Conn PJ (2007) A novel family of potent negative allosteric modulators of group II metabotropic glutamate receptors. J Pharmacol Exp Ther 322:254-264.
56. Hemstapat K, de Paulis T, Chen Y, Brady AE, Grover VK, Alagille D, Tamagnan GD, and Conn PJ (2006) 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 70:616-626.
57. Hughes ZA, Neal SJ, Smith DL, Sukoff Rizzo SJ, Pulicicchio CM, Lotarski S, Lu S, Dwyer JM, Brennan J, and Olsen M et al. (2013) Negative allosteric modulation of metabotropic glutamate receptor 5 results in broad spectrum activity relevant to treatment resistant depression. Neuropharmacology 66:202-214.
58. Iacovelli L, Felicioni M, Nisticò R, Nicoletti F, and De Blasi A (2014) Selective regulation of recombinantly expressed mGlu7 metabotropic glutamate receptors by G protein-coupled receptor kinases and arrestins. Neuropharmacology 77:303-312.
59. Jalan-Sakrikar N, Field JR, Klar R, Mattmann ME, Gregory KJ, Zamorano R, Engers DW, Bollinger SR, Weaver CD, and Days EL et al. (2014) Identification of positive allosteric modulators VU0155094 (ML397) and VU0422288 (ML396) reveals new insights into the biology of metabotropic glutamate receptor 7. ACS Chem Neurosci 5:1221-1237.
60. Jiang JY, Nagaraju M, Meyer RC, Zhang L, Hamelberg D, Hall RA, Brown EM, Conn PJ, and Yang JJ (2014) Extracellular calcium modulates actions of orthosteric and allosteric ligands on metabotropic glutamate receptor 1a. J Biol Chem 289:1649-1661.
61. Johnson MP, Barda D, Britton TC, Emkey R, Hornback WJ, Jagdmann GE, McKinzie DL, Nisenbaum ES, Tizzano JP, and Schoepp DD (2005) Metabotropic glutamate 2 receptor potentiators: receptor modulation, frequency-dependent synaptic activity, and efficacy in preclinical anxiety and psychosis model(s). Psychopharmacology (Berl) 179:271-283.
62. Jones CK, Bubser M, Thompson AD, Dickerson JW, Turle-Lorenzo N, Amalric M, Blobaum AL, Bridges TM, Morrison RD, and Jadhav S et al. (2012) The metabotropic glutamate receptor 4-positive allosteric modulator VU0364770 produces efficacy alone and in combination with L-DOPA or an adenosine 2A antagonist in preclinical rodent models of Parkinson's disease. J Pharmacol Exp Ther 340:404-421.
63. Jones PJ, Xiang Z, and Conn PJ (2008) Metabotropic glutamate receptors mGluR4 and mGluR8 regulate transmission in the lateral olfactory tract-piriform cortex synapse. Neuropharmacology 55:440-446.
64. Jong YJ, Kumar V, Kingston AE, Romano C, and O'Malley KL (2005) Functional metabotropic glutamate receptors on nuclei from brain and primary cultured striatal neurons. Role of transporters in delivering ligand. J Biol Chem 280:30469-30480.
65. Jong YJ, Kumar V, and O'Malley KL (2009) Intracellular metabotropic glutamate receptor 5 (mGluR5) activates signaling cascades distinct from cell surface counterparts. J Biol Chem 284:35827-35838.
66. Julio-Pieper M, Flor PJ, Dinan TG, and Cryan JF (2011) Exciting times beyond the brain: metabotropic glutamate receptors in peripheral and non-neural tissues. Pharmacol Rev 63:35-58.
67. Kalinichev M, Rouillier M, Girard F, Royer-Urios I, Bournique B, Finn T, Charvin D, Campo B, Le Poul E, and Mutel V et al. (2013) ADX71743, a potent and selective negative allosteric modulator of metabotropic glutamate receptor 7: in vitro and in vivo characterization. J Pharmacol Exp Ther 344:624-636.
68. Kammermeier PJ (2012) Functional and pharmacological characteristics of metabotropic glutamate receptors 2/4 heterodimers. Mol Pharmacol 82:438-447.
69. Keywood C, Wakefield M, and Tack J (2009) 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 58:1192-1199.
70. Kinney GG, O'Brien JA, Lemaire W, Burno M, Bickel DJ, Clements MK, Chen TB, Wisnoski DD, Lindsley CW, and Tiller PR et al. (2005) A novel selective positive allosteric modulator of metabotropic glutamate receptor subtype 5 has in vivo activity and antipsychotic-like effects in rat behavioral models. J Pharmacol Exp Ther 313:199-206.
71. Kinon BJ, Zhang L, Millen BA, Osuntokun OO, Williams JE, Kollack-Walker S, Jackson K, Kryzhanovskaya L, and Jarkova N; HBBI Study Group (2011) A multicenter, inpatient, phase 2, double-blind, placebo-controlled dose-ranging study of LY2140023 monohydrate in patients with DSM-IV schizophrenia. J Clin Psychopharmacol 31:349-355.
72. Knoflach F, Mutel V, Jolidon S, Kew JN, Malherbe P, Vieira E, Wichmann J, and Kemp JA (2001) Positive allosteric modulators of metabotropic glutamate 1 receptor: characterization, mechanism of action, and binding site. Proc Natl Acad Sci USA 98:13402-13407.
73. Kohara A, Toya T, Tamura S, Watabiki T, Nagakura Y, Shitaka Y, Hayashibe S, Kawabata S, and Okada M (2005) Radioligand binding properties and pharmacological characterization of 6-amino-N-cyclohexyl-N,3-dimethylthiazolo[3,2-a] benzimidazole-2-carboxamide (YM-298198), a high-affinity, selective, and non-competitive antagonist of metabotropic glutamate receptor type 1. J Pharmacol Exp Ther 315:163-169.
74. Kruse AC, Ring AM, Manglik A, Hu J, Hu K, Eitel K, Hübner H, Pardon E, Valant C, and Sexton PM et al. (2013) Activation and allosteric modulation of a muscarinic acetylcholine receptor. Nature 504:101-106.
75. Kumar V, Fahey PG, Jong YJ, Ramanan N, and O'Malley KL (2012) Activation of intracellular metabotropic glutamate receptor 5 in striatal neurons leads to up-regulation of genes associated with sustained synaptic transmission including Arc/Arg3.1 protein. J Biol Chem 287:5412-5425.
76. Kumar V, Jong YJ, and O'Malley KL (2008) Activated nuclear metabotropic glutamate receptor mGlu5 couples to nuclear Gq/11 proteins to generate inositol 1,4,5-trisphosphate-mediated nuclear Ca2+ release. J Biol Chem 283:14072-14083.
77. Lamb JP, Engers DW, Niswender CM, Rodriguez AL, Venable DF, Conn PJ, and Lindsley CW (2011) Discovery of molecular switches within the ADX-47273 mGlu5 PAM scaffold that modulate modes of pharmacology to afford potent mGlu5 NAMs, PAMs and partial antagonists. Bioorg Med Chem Lett 21:2711-2714.
78. Lavreysen H, Janssen C, Bischoff F, Langlois X, Leysen JE, and Lesage AS (2003) [3H]R214127: a novel high-affinity radioligand for the mGlu1 receptor reveals a common binding site shared by multiple allosteric antagonists. Mol Pharmacol 63:1082-1093.
79. Lavreysen H, Langlois X, Ahnaou A, Drinkenburg W, te Riele P, Biesmans I, Van der Linden I, Peeters L, Megens A, and Wintmolders C et al. (2013) Pharmacological characterization of JNJ-40068782, a new potent, selective, and systemically active positive allosteric modulator of the mGlu2 receptor and its radioligand [3H]JNJ-40068782. J Pharmacol Exp Ther 346:514-527.
80. Lavreysen H, Wouters R, Bischoff F, Nóbrega Pereira S, Langlois X, Blokland S, Somers M, Dillen L, and Lesage AS (2004) JNJ16259685, a highly potent, selective and systemically active mGlu1 receptor antagonist. Neuropharmacology 47:961-972.
81. Li X, Need AB, Baez M, and Witkin JM (2006) Metabotropic glutamate 5 receptor antagonism is associated with antidepressant-like effects in mice. J Pharmacol Exp Ther 319:254-259.
82. Lindsley CW (2014) 2013 Philip S. Portoghese Medicinal Chemistry Lectureship: drug discovery targeting allosteric sites. J Med Chem 57:7485-7498.
83. Litschig S, Gasparini F, Rueegg D, Stoehr N, Flor PJ, Vranesic I, Prézeau L, Pin JP, Thomsen C, and Kuhn R (1999) CPCCOEt, a noncompetitive metabotropic glutamate receptor 1 antagonist, inhibits receptor signaling without affecting glutamate binding. Mol Pharmacol 55:453-461.
84. Lundström L, Bissantz C, Beck J, Wettstein JG, Woltering TJ, Wichmann J, and Gatti S (2011) Structural determinants of allosteric antagonism at metabotropic glutamate receptor 2: mechanistic studies with new potent negative allosteric modulators. Br J Pharmacol 164 (2b):521-537.
85. Ma AWS, Redka DS, Pisterzi LF, Angers S, and Wells JW (2007) Recovery of oligomers and cooperativity when monomers of the M2 muscarinic cholinergic receptor are reconstituted into phospholipid vesicles. Biochemistry 46:7907-7927.
86. Mabire D, Coupa S, Adelinet C, Poncelet A, Simonnet Y, Venet M, Wouters R, Lesage AS, Van Beijsterveldt L, and Bischoff F (2005) Synthesis, structure-activity relationship, and receptor pharmacology of a new series of quinoline derivatives acting as selective, noncompetitive mGlu1 antagonists. J Med Chem 48:2134-2153.
87. Maj M, Bruno V, Dragic Z, Yamamoto R, Battaglia G, Inderbitzin W, Stoehr N, Stein T, Gasparini F, and Vranesic I et al. (2003) (-)-PHCCC, a positive allosteric modulator of mGluR4: characterization, mechanism of action, and neuroprotection. Neuropharmacology 45:895-906.
88. Malherbe P, Kratochwil N, Knoflach F, Zenner MT, Kew JN, Kratzeisen C, Maerki HP, Adam G, and Mutel V (2003a) Mutational analysis and molecular modeling of the allosteric binding site of a novel, selective, noncompetitive antagonist of the metabotropic glutamate 1 receptor. J Biol Chem 278:8340-8347.
89. Malherbe P, Kratochwil N, Mühlemann A, Zenner M-T, Fischer C, Stahl M, Gerber PR, Jaeschke G, and Porter RHP (2006) 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 98:601-615.
90. Malherbe P, Kratochwil N, Zenner MT, Piussi J, Diener C, Kratzeisen C, Fischer C, and Porter RH (2003b) Mutational analysis and molecular modeling of the binding pocket of the metabotropic glutamate 5 receptor negative modulator 2-methyl-6-(phenylethynyl)-pyridine. Mol Pharmacol 64:823-832.
91. Marino MJ, Williams DL, Jr, O'Brien JA, Valenti O, McDonald TP, Clements MK, Wang R, DiLella AG, Hess JF, and Kinney GG et al. (2003) Allosteric modulation of group III metabotropic glutamate receptor 4: a potential approach to Parkinson's disease treatment. Proc Natl Acad Sci USA 100:13668-13673.
92. Mathiesen JM, Svendsen N, Bräuner-Osborne H, Thomsen C, and Ramirez MT (2003) Positive allosteric modulation of the human metabotropic glutamate receptor 4 (hmGluR4) by SIB-1893 and MPEP. Br J Pharmacol 138:1026-1030.
93. Mitsukawa K, Yamamoto R, Ofner S, Nozulak J, Pescott O, Lukic S, Stoehr N, Mombereau C, Kuhn R, and McAllister KH et al. (2005) A selective metabotropic glutamate receptor 7 agonist: activation of receptor signaling via an allosteric site modulates stress parameters in vivo. Proc Natl Acad Sci USA 102:18712-18717.
94. Moghaddam B (2004) Targeting metabotropic glutamate receptors for treatment of the cognitive symptoms of schizophrenia. Psychopharmacology (Berl) 174:39-44.
95. Mølck C, Harpsøe K, Gloriam DE, Clausen RP, Madsen U, Pedersen LO, Jimenez HN, Nielsen SM, Mathiesen JM, and Bräuner-Osborne H (2012) Pharmacological characterization and modeling of the binding sites of novel 1,3-bis(pyridinylethynyl)benzenes as metabotropic glutamate receptor 5-selective negative allosteric modulators. Mol Pharmacol 82:929-937.
96. Moussawi K and Kalivas PW (2010) Group II metabotropic glutamate receptors (mGlu2/3) in drug addiction. Eur J Pharmacol 639:115-122.
97. Mühlemann A, Ward NA, Kratochwil N, Diener C, Fischer C, Stucki A, Jaeschke G, Malherbe P, and Porter RH (2006) Determination of key amino acids implicated in the actions of allosteric modulation by 3,39-difluorobenzaldazine on rat mGlu5 receptors. Eur J Pharmacol 529:95-104.
98. Niswender CM, Johnson KA, Miller NR, Ayala JE, Luo Q, Williams R, Saleh S, Orton D, Weaver CD, and Conn PJ (2010) Context-dependent pharmacology exhibited by negative allosteric modulators of metabotropic glutamate receptor 7. Mol Pharmacol 77:459-468.
99. Niswender CM, Johnson KA, Weaver CD, Jones CK, Xiang Z, Luo Q, Rodriguez AL, Marlo JE, de Paulis T, and Thompson AD et al. (2008) Discovery, characterization, and antiparkinsonian effect of novel positive allosteric modulators of metabotropic glutamate receptor 4. Mol Pharmacol 74:1345-1358.
100. Noetzel MJ, Gregory KJ, Vinson PN, Manka JT, Stauffer SR, Lindsley CW, Niswender CM, Xiang Z, and Conn PJ (2013) A novel metabotropic glutamate receptor 5 positive allosteric modulator acts at a unique site and confers stimulus bias to mGlu5 signaling. Mol Pharmacol 83:835-847.
101. Noetzel MJ, Jones CK, and Conn PJ (2012a) Emerging approaches for treatment of schizophrenia: modulation of glutamatergic signaling. Discov Med 14:335-343.
102. Noetzel MJ, Rook JM, Vinson PN, Cho HP, Days E, Zhou Y, Rodriguez AL, Lavreysen H, Stauffer SR, and Niswender CM et al. (2012b) Functional impact of allosteric agonist activity of selective positive allosteric modulators of metabotropic glutamate receptor subtype 5 in regulating central nervous system function. Mol Pharmacol 81:120-133.
103. O'Brien JA, Lemaire W, Chen TB, Chang RS, Jacobson MA, Ha SN, Lindsley CW, Schaffhauser HJ, Sur C, and Pettibone DJ et al. (2003) A family of highly selective allosteric modulators of the metabotropic glutamate receptor subtype 5. Mol Pharmacol 64:731-740.
104. O'Brien JA, Lemaire W, Wittmann M, Jacobson MA, Ha SN, Wisnoski DD, Lindsley CW, Schaffhauser HJ, Rowe B, and Sur C et al. (2004) A novel selective allosteric modulator potentiates the activity of native metabotropic glutamate receptor subtype 5 in rat forebrain. J Pharmacol Exp Ther 309:568-577.
105. Odagaki Y, Kinoshita M, and Toyoshima R (2011) Functional coupling between metabotropic glutamate receptors and G-proteins in rat cerebral cortex assessed by guanosine-5′-O-(3-[(35)S]thio)triphosphate binding assay. Basic Clin Pharmacol Toxicol 109:175-185.
106. Odagaki Y, Kinoshita M, and Toyoshima R (2013) Group II metabotropic glutamate receptor-mediated activation of G-proteins in rat hippocampal and striatal membranes. Neurosci Lett 539:22-26.
107. Ott D, Floersheim P, Inderbitzin W, Stoehr N, Francotte E, Lecis G, Richert P, Rihs G, Flor PJ, and Kuhn R et al. (2000) Chiral resolution, pharmacological characterization, and receptor docking of the noncompetitive mGlu1 receptor antagonist (+/-)-2-hydroxyimino- 1a, 2-dihydro-1H-7-oxacyclopropa[b]naphthalene-7a-carboxylic acid ethyl ester. J Med Chem 43:4428-4436.
108. Pagano A, Ruegg D, Litschig S, Stoehr N, Stierlin C, Heinrich M, Floersheim P, Prezèau L, Carroll F, and Pin JP et al. (2000) The non-competitive antagonists 2-methyl-6-(phenylethynyl)pyridine and 7-hydroxyiminocyclopropan[b]chromen-1a-carboxylic acid ethyl ester interact with overlapping binding pockets in the transmembrane region of group I metabotropic glutamate receptors. J Biol Chem 275:33750-33758.
109. Parmentier-Batteur S, Hutson PH, Menzel K, Uslaner JM, Mattson BA, O'Brien JA, Magliaro BC, Forest T, Stump CA, and Tynebor RM et al. (2014) Mechanism based neurotoxicity of mGlu5 positive allosteric modulators - development challenges for a promising novel antipsychotic target. Neuropharmacology 82:161-173.
110. Patil ST, Zhang L, Martenyi F, Lowe SL, Jackson KA, Andreev BV, Avedisova AS, Bardenstein LM, Gurovich IY, and Morozova MA et al. (2007) Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial. Nat Med 13:1102-1107.
111. Pelkey KA, Yuan X, Lavezzari G, Roche KW, and McBain CJ (2007) mGluR7 undergoes rapid internalization in response to activation by the allosteric agonist AMN082. Neuropharmacology 52:108-117.
112. Pinheiro PS and Mulle C (2008) Presynaptic glutamate receptors: physiological functions and mechanisms of action. Nat Rev Neurosci 9:423-436.
113. Pittolo S, Gómez-Santacana X, Eckelt K, Rovira X, Dalton J, Goudet C, Pin JP, Llobet A, Giraldo J, and Llebaria A et al. (2014) An allosteric modulator to control endogenous G protein-coupled receptors with light. Nat Chem Biol 10:813-815.
114. Porter RH, Jaeschke G, Spooren W, Ballard TM, Büttelmann B, Kolczewski S, Peters JU, Prinssen E, Wichmann J, and Vieira E et al. (2005) Fenobam: a clinically validated nonbenzodiazepine anxiolytic is a potent, selective, and noncompetitive mGlu5 receptor antagonist with inverse agonist activity. J Pharmacol Exp Ther 315:711-721.
115. Purgert CA, Izumi Y, Jong YJ, Kumar V, Zorumski CF, and O'Malley KL (2014) Intracellular mGluR5 can mediate synaptic plasticity in the hippocampus. J Neurosci 34:4589-4598.
116. Rodriguez AL, Grier MD, Jones CK, Herman EJ, Kane AS, Smith RL, Williams R, Zhou Y, Marlo JE, and Days EL et al. (2010) 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 78:1105-1123.
117. Rodriguez AL, Nong Y, Sekaran NK, Alagille D, Tamagnan GD, and Conn PJ (2005) A close structural analog of 2-methyl-6-(phenylethynyl)-pyridine acts as a neutral allosteric site ligand on metabotropic glutamate receptor subtype 5 and blocks the effects of multiple allosteric modulators. Mol Pharmacol 68:1793-1802.
118. Rodriguez AL, Zhou Y, Williams R, Weaver CD, Vinson PN, Dawson ES, Steckler T, Lavreysen H, Mackie C, and Bartolomé JM et al. (2012) Discovery and SAR of a novel series of non-MPEP site mGlu5 PAMs based on an aryl glycine sulfonamide scaffold. Bioorg Med Chem Lett 22:7388-7392.
119. Rook JM, Noetzel MJ, Pouliot WA, Bridges TM, Vinson PN, Cho HP, Zhou Y, Gogliotti RD, Manka JT, and Gregory KJ et al. (2013) Unique signaling profiles of positive allosteric modulators of metabotropic glutamate receptor subtype 5 determine differences in in vivo activity. Biol Psychiatry 73:501-509.
120. Rook JM, Xiang Z, Lv X, Ghoshal A, Dickerson JW, Bridges TM, Johnson KA, Foster DJ, Gregory KJ, and Vinson PN et al. (2015) Biased mGlu5 positive allosteric modulators provide in vivo efficacy without potentiating mGlu5 modulation of NMDAR currents. Neuron, in press.
121. Rovira X, Malhaire F, Scholler P, Rodrigo J, Gonzalez-Bulnes P, Llebaria A, Pin JP, Giraldo J, and Goudet C (2015) Overlapping binding sites drive allosteric agonism and positive cooperativity in type 4 metabotropic glutamate receptors. FASEB J 29:116-130.
122. Rowe BA, Schaffhauser H, Morales S, Lubbers LS, Bonnefous C, Kamenecka TM, McQuiston J, and Daggett LP (2008) Transposition of three amino acids transforms the human metabotropic glutamate receptor (mGluR)-3-positive allosteric modulation site to mGluR2, and additional characterization of the mGluR2-positive allosteric modulation site. J Pharmacol Exp Ther 326:240-251.
123. Rylander D, Iderberg H, Li Q, Dekundy A, Zhang J, Li H, Baishen R, Danysz W, Bezard E, and Cenci MA (2010) A mGluR5 antagonist under clinical development improves L-DOPA-induced dyskinesia in parkinsonian rats and monkeys. Neurobiol Dis 39:352-361.
124. Sams AG, Mikkelsen GK, Brodbeck RM, Pu X, and Ritzén A (2011) Efficacy switching SAR of mGluR5 allosteric modulators: highly potent positive and negative modulators from one chemotype. Bioorg Med Chem Lett 21:3407-3410.
125. Sanger H, Hanna L, Colvin EM, Grubisha O, Ursu D, Heinz BA, Findlay JD, Vivier RG, Sher E, and Lodge D et al. (2013) Pharmacological profiling of native group II metabotropic glutamate receptors in primary cortical neuronal cultures using a FLIPR. Neuropharmacology 66:264-273.
126. Scandroglio P, Brusa R, Lozza G, Mancini I, Petrò R, Reggiani A, and Beltramo M (2010) Evaluation of cannabinoid receptor 2 and metabotropic glutamate receptor 1 functional responses using a cell impedance-based technology. J Biomol Screen 15:1238-1247.
127. Schaffhauser H, Rowe BA, Morales S, Chavez-Noriega LE, Yin R, Jachec C, Rao SP, Bain G, Pinkerton AB, and Vernier JM et al. (2003) Pharmacological characterization and identification of amino acids involved in the positive modulation of metabotropic glutamate receptor subtype 2. Mol Pharmacol 64:798-810.
128. Schann S, Mayer S, Franchet C, Frauli M, Steinberg E, Thomas M, Baron L, and Neuville P (2010) 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 53:8775-8779.
129. Schoepp DD, Wright RA, Levine LR, Gaydos B, and Potter WZ (2003) LY354740, an mGlu2/3 receptor agonist as a novel approach to treat anxiety/stress. Stress 6:189-197.
130. Sevastyanova TN and Kammermeier PJ (2014) Cooperative signaling between homodimers of metabotropic glutamate receptors 1 and 5. Mol Pharmacol 86:492-504.
131. Sharma S, Kedrowski J, Rook JM, Smith RL, Jones CK, Rodriguez AL, Conn PJ, and Lindsley CW (2009) 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 52:4103-4106.
132. Sheffler DJ and Conn PJ (2008) Allosteric potentiators of metabotropic glutamate receptor subtype 1a differentially modulate independent signaling pathways in baby hamster kidney cells. Neuropharmacology 55:419-427.
133. Sheffler DJ, Wenthur CJ, Bruner JA, Carrington SJS, Vinson PN, Gogi KK, Blobaum AL, Morrison RD, Vamos M, and Cosford NDP et al. (2012) Development of a novel, CNS-penetrant, metabotropic glutamate receptor 3 (mGlu3) NAM probe (ML289) derived from a closely related mGlu5 PAM. Bioorg Med Chem Lett 22:3921-3925.
134. Sukoff Rizzo SJ, Leonard SK, Gilbert A, Dollings P, Smith DL, Zhang MY, Di L, Platt BJ, Neal S, and Dwyer JM et al. (2011) The metabotropic glutamate receptor 7 allosteric modulator AMN082: a monoaminergic agent in disguise? J Pharmacol Exp Ther 338:345-352.
135. Surin A, Pshenichkin S, Grajkowska E, Surina E, and Wroblewski JT (2007) Cyclothiazide selectively inhibits mGluR1 receptors interacting with a common allosteric site for non-competitive antagonists. Neuropharmacology 52:744-754.
136. Suzuki G, Kimura T, Satow A, Kaneko N, Fukuda J, Hikichi H, Sakai N, Maehara S, Kawagoe-Takaki H, and Hata M et al. (2007) Pharmacological characterization of a new, orally active and potent allosteric metabotropic glutamate receptor 1 antagonist, 4-[1-(2-fluoropyridin-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide (FTIDC). J Pharmacol Exp Ther 321:1144-1153.
137. Treyer V, Streffer J, Wyss MT, Bettio A, Ametamey SM, Fischer U, Schmidt M, Gasparini F, Hock C, and Buck A (2007) Evaluation of the metabotropic glutamate receptor subtype 5 using PET and 11C-ABP688: assessment of methods. J Nucl Med 48:1207-1215.
138. Turlington M, Noetzel MJ, Bridges TM, Vinson PN, Steckler T, Lavreysen H, Mackie C, Bartolomé-Nebreda JM, Conde-Ceide S, and Tong HM et al. (2014) Discovery and SAR of a novel series of metabotropic glutamate receptor 5 positive allosteric modulators with high ligand efficiency. Bioorg Med Chem Lett 24:3641-3646.
139. Valenti O, Conn PJ, and Marino MJ (2002) Distinct physiological roles of the Gq-coupled metabotropic glutamate receptors Co-expressed in the same neuronal populations. J Cell Physiol 191:125-137.
140. Valenti O, Mannaioni G, Seabrook GR, Conn PJ, and Marino MJ (2005) Group III metabotropic glutamate-receptor-mediated modulation of excitatory transmission in rodent substantia nigra pars compacta dopamine neurons. J Pharmacol Exp Ther 313:1296-1304.
141. Vieira E, Huwyler J, Jolidon S, Knoflach F, Mutel V, and Wichmann J (2009) Fluorinated 9H-xanthene-9-carboxylic acid oxazol-2-yl-amides as potent, orally available mGlu1 receptor enhancers. Bioorg Med Chem Lett 19:1666-1669.
142. Vilar B, Busserolles J, Ling B, Laffray S, Ulmann L, Malhaire F, Chapuy E, Aissouni Y, Etienne M, and Bourinet E et al. (2013) Alleviating pain hypersensitivity through activation of type 4 metabotropic glutamate receptor. J Neurosci 33:18951-18965.
143. Woltering TJ, Wichmann J, Goetschi E, Knoflach F, Ballard TM, Huwyler J, and Gatti S (2010) Synthesis and characterization of 1,3-dihydro-benzo[b][1,4] diazepin-2-one derivatives: Part 4. In vivo active potent and selective non-competitive metabotropic glutamate receptor 2/3 antagonists. Bioorg Med Chem Lett 20:6969-6974.
144. Wood MR, Hopkins CR, Brogan JT, Conn PJ, and Lindsley CW (2011) "Molecular switches" on mGluR allosteric ligands that modulate modes of pharmacology. Biochemistry 50:2403-2410.
145. Wu H, Wang C, Gregory KJ, Han GW, Cho HP, Xia Y, Niswender CM, Katritch V, Meiler J, and Cherezov V et al. (2014) Structure of a class C GPCR metabotropic glutamate receptor 1 bound to an allosteric modulator. Science 344:58-64.
146. Yin S, Noetzel MJ, Johnson KA, Zamorano R, Jalan-Sakrikar N, Gregory KJ, Conn PJ, and Niswender CM (2014) Selective actions of novel allosteric modulators reveal functional heteromers of metabotropic glutamate receptors in the CNS. J Neurosci 34:79-94.
147. Yin S, Zamorano R, Conn PJ, and Niswender CM (2013) Functional selectivity induced by mGlu(4) receptor positive allosteric modulation and concomitant activation of G(q) coupled receptors. Neuropharmacology 66:122-132.
148. Zerbib F, Keywood C, and Strabach G (2010) Efficacy, tolerability and pharmacokinetics of a modified release formulation of ADX10059, a negative allosteric modulator of metabotropic glutamate receptor 5: an esophageal pH-impedance study in healthy subjects. Neurogastroenterol Motil 22: 859-865.
149. Zhang Y, Rodriguez AL, and Conn PJ (2005) Allosteric potentiators of metabotropic glutamate receptor subtype 5 have differential effects on different signaling pathways in cortical astrocytes. J Pharmacol Exp Ther 315:1212-1219.
150. Zhou Y, Manka JT, Rodriguez AL, Weaver CD, Days EL, Vinson PN, Jadhav S, Hermann EJ, Jones CK, and Conn PJ et al. (2010) Discovery of N-Aryl Piperazines as Selective mGlu(5) Potentiators with Efficacy in a Rodent Model Predictive of Anti-Psychotic Activity. ACS Med Chem Lett 1:433-438.