Preferential binding of allosteric modulators to active and inactive conformational states of metabotropic glutamate receptors

BMC Bioinformatics

Volumn 9, Issue SUPPL. 1, 2008, Pages

  Yanamala, Naveena ^a   Tirupula, Kalyan C ^a   Klein Seetharaman, Judith ^a  

^a UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALLOSTERIC MODULATION; ALLOSTERIC MODULATORS; CONFORMATIONAL STATE; G PROTEIN COUPLED RECEPTORS; METABOTROPIC GLUTAMATE RECEPTORS; PHOTOCHEMICAL ISOMERIZATION; PREFERENTIAL BINDING; TRANSMEMBRANE REGIONS; ALLOSTERIC EFFECT; AUTODOCK; COMPUTATIONAL MODEL; DARK STATE; DOCKING PROGRAMS; DRUG TARGETS; LIGAND BINDING; PATHOLOGICAL PROCESS; RETINAL BINDING; SYNAPTIC PLASTICITY;

CONFORMATIONS; MODULATION; OPHTHALMOLOGY; BIOINFORMATICS;

LIGANDS;

METABOTROPIC RECEPTOR; RHODOPSIN;

ALLOSTERISM; AMINO ACID SEQUENCE; ARTICLE; BINDING KINETICS; COMPUTER MODEL; COMPUTER PROGRAM; CONTROLLED STUDY; CORRELATION FUNCTION; CRYSTAL STRUCTURE; HYPOTHESIS; ISOMERIZATION; LIGAND BINDING; PROTEIN CONFORMATION; RECEPTOR BINDING; ALGORITHM; BINDING SITE; CHEMICAL MODEL; CHEMICAL STRUCTURE; CHEMISTRY; COMPUTER SIMULATION; ISOMERISM; METHODOLOGY; MOLECULAR GENETICS; PROTEIN BINDING; SEQUENCE ANALYSIS; STRUCTURE ACTIVITY RELATION; ULTRASTRUCTURE;

ALGORITHMS; AMINO ACID SEQUENCE; BINDING SITES; COMPUTER SIMULATION; ISOMERISM; MODELS, CHEMICAL; MODELS, MOLECULAR; MOLECULAR SEQUENCE DATA; PROTEIN BINDING; PROTEIN CONFORMATION; RECEPTORS, METABOTROPIC GLUTAMATE; SEQUENCE ANALYSIS, PROTEIN; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84871967847     PISSN: None     EISSN: 14712105     Source Type: Journal    
DOI: 10.1186/1471-2105-9-S1-S16     Document Type: Article

References (83)

1. Swanson CJ Bures M Johnson MP Linden AM Monn JA Schoepp DD Metabotropic glutamate receptors as novel targets for anxiety and stress disorders Nat Rev Drug Discov 2005, 4(2):131-44. 15665858 10.1038/nrd1630
2. Kew JN Positive and negative allosteric modulation of metabotropic glutamate receptors: Emerging therapeutic potential Pharmacol Ther 2004, 104(3):233-44. 15556676 10.1016/j.pharmthera.2004.08.010
3. Dryja TP McGee TL Berson EL Fishman GA Sandberg MA Alexander KR Derlacki DJ Rajagopalan AS Night blindness and abnormal cone electroretinogram ON responses in patients with mutations in the GRM6 gene encoding mGluR6 Proc Natl Acad Sci USA 2005, 102(13):4884-9. 15781871 10.1073/ pnas.0501233102 555731
4. Parmentier ML Prézeau L Bockaert J Pin JP A model for the functioning of family 3 GPCRs Trends Pharmacol Sci 2002, 23(6):268-74. 12084632 10.1016/S0165-6147(02)02016-3
5. 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):971-7. 11069170 10.1038/35039564
6. 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):2660-5. 11867751 10.1073/pnas.052708599 122404
7. Hampson DR Huang XP Pekhletski R Peltekova V Hornby G Thomsen C Thogersen H Probing the ligand-binding domain of the mGluR4 subtype of metabotropic glutamate receptor J Biol Chem 1999, 274(47):33488-95. 10559233 10.1074/jbc.274.47.33488
8. 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):3759-64. 17360426 10.1073/pnas.0611577104 1820657
9. Armstrong N Sun Y Chen GQ Gouaux E Structure of a glutamate-receptor ligand-binding core in complex with kainate Nature 1998, 395(6705):913-7. 9804426 10.1038/27692
10. Armstrong N Gouaux E Mechanisms for activation and antagonism of an AMPA-sensitive glutamate receptor: Crystal structures of the GluR2 ligand binding core 118 Neuron 2000, 28(1):165-81. 11086992 10.1016/ S0896-6273(00)00094-5
11. Mayer ML Glutamate receptors at atomic resolution Nature 2006, 440(7083):456-62. 16554805 10.1038/nature04709
12. Conn PJ Pin JP Pharmacology and functions of metabotropic glutamate receptors Annu Rev Pharmacol Toxicol 1997, 37:205-37. 9131252 10.1146/ annurev.pharmtox.37.1.205
13. Malherbe P Kratochwil N Knoflach F Zenner MT Kew JN Kratzeisen C Maerki HP Adam G Mutel V 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 2003, 278(10):8340-7. 12509432 10.1074/jbc.M211759200
14. Malherbe P Kratochwil N Zenner MT Piussi J Diener C Kratzeisen C Fischer C Porter RH Mutational analysis and molecular modeling of the binding pocket of the metabotropic glutamate 5 receptor negative modulator 2-methyl-6-(phenylethynyl)-pyridine Mol Pharmacol 2003, 64(4):823-32. 14500738 10.1124/mol.64.4.823
15. Goudet C Gaven F Kniazeff J Vol C Liu J Cohen-Gonsaud M Acher F Prézeau L Pin LP Heptahelical domain of metabotropic glutamate receptor 5 behaves like rhodopsin-like receptors Proc Natl Acad Sci USA 2004, 101(1):378-83. 14691258 10.1073/pnas.0304699101 314193
16. O'Brien JA Lemaire W Chen TB Chang RS Jacobson MA Ha SN Lindsley CW Schaffhauser HJ Sur C Pettibone DJ Conn PJ Williams DL Jr A family of highly selective allosteric modulators of the metabotropic glutamate receptor subtype 5 Mol Pharmacol 2003, 64(3):731-40. 12920211 10.1124/ mol.64.3.731
17. Palczewski K Kumasaka T Hori T Behnke CA Motoshima H Fox BA Le Trong I Teller DC Okada T Stenkamp RE Yamamoto M Miyano M Crystal structure of rhodopsin: A G protein-coupled receptor Science 2000, 289(5480):739-45. 10926528 10.1126/science.289.5480.739
18. Isin B Rader AJ Dhiman HK Klein-Seetharaman J Bahar I Predisposition of the dark state of rhodopsin to functional changes in structure Proteins 2006, 65(4):970-83. 17009319 10.1002/prot.21158
19. Muhlemann A Ward NA Kratochwil N Diener C Fischer C Stucki A Jaeschke G Malherbe P Porter RH Determination of key amino acids implicated in the actions of allosteric modulation by 3,3'-difluorobenzaldazine on rat mGlu5 receptors Eur J Pharmacol 2006, 529(1-3):95-104. 16352303 10.1016/ j.ejphar.2005.11.008
20. Man O Gilad Y Lancet D Prediction of the odorant binding site of olfactory receptor proteins by human-mouse comparisons Protein Sci 2004, 13(1):240-54. 14691239 10.1110/ps.03296404
21. Miedlich SU Gama L Seuwen K Wolf RM Breitwiesser GE Homology modeling of the transmembrane domain of the human calcium sensing receptor and localization of an allosteric binding site J Biol Chem 2004, 279(8):7254-63. 14660633 10.1074/jbc.M307191200
22. Kim S Chamberlain AK Bowie JU A simple method for modeling transmembrane helix oligomers J Mol Biol 2003, 329(4):831-40. 12787681 10.1016/ S0022-2836(03)00521-7
23. Petrel C Kessler A Maslah F Dauban P Dodd RH Rognan D Ruat M Modeling and mutagenesis of the binding site of Calhex 231, a novel negative allosteric modulator of the extracellular Ca(2+)-sensing receptor J Biol Chem 2003, 278(49):49487-94. 14506236 10.1074/jbc.M308010200
24. Ruan KH Wu J So SP Jenkins LA Evidence of the residues involved in ligand recognition in the second extracellular loop of the prostacyclin receptor characterized by high resolution 2D NMR techniques Arch Biochem Biophys 2003, 418(1):25-33. 13679079 10.1016/S0003-9861(03)00401-6
25. Axe FU Bembenek SD Szalma S Three-dimenstional models of histamine H3 receptor antagonist complexes and their pharamcophore J Mol Graph Model 2006, 24(6):456-464. 14673104 10.1073/pnas.2136795100 307612
26. Berkhout TA Blaney FE Bridges AM Cooper DG Forbes IT Gribble AD Groot PH Hardy A Ife RJ Kaur R Moores KE Shillito H Wiletts J Witherington J CCR2: Characterization of the antagonist binding site from a combined receptor modeling/mutagenesis approach J Med Chem 2003, 46(19):4070-86. 12954060 10.1021/jm030862l
27. Anzini M Canullo L Braile C Cappelli A Gallelli A Vomero S Menziani MC De Benedetti PG Rizzo M Collina S Azzolina O Sbacchi M Ghelardini C Galeotti N Synthesis, biological evaluation, and receptor docking simulations of 2-[(acylamino)ethyl]-1,4-benzodiazepines as kappa-opioid receptor agonists endowed with antinociceptive and antiamnesic activity J Med Chem 2003, 46(18):3853-64. 12930147 10.1021/jm0307640
28. Hulme EC Lu ZL Bee MS Scanning mutagenesis studies of the M1 muscarinic acetylcholine receptor Receptors Channels 2003, 9(4):215-28. 12893535 10.1080/10606820308261
29. Schulz A Schoneberg T The structural evolution of a P2Y-like G-protein-coupled receptor J Biol Chem 2003, 278(37):35531-41. 12835326 10.1074/jbc.M303346200
30. Becker OM Shacham S Marantz Y Noiman S Modeling the 3D structure of GPCRs: Advances and application to drug discovery Curr Opin Drug Discov Devel 2003, 6(3):353-61. 12833668
31. Mehler EL Periole X Hassan SA Weinstein H Key issues in the computational simulation of GPCR function: Representation of loop domains J Comput Aided Mol Des 2002, 16(11):841-53. 12825797 10.1023/ A:1023845015343
32. Johren K Holtje HD A model of the human M2 muscarinic acetylcholine receptor J Comput Aided Mol Des 2002, 16(11):795-801. 12825791 10.1023/ A:1023880611709
33. Shim JY Welsh WJ Howlett AC Homology model of the CB1 cannabinoid receptor: Sites critical for nonclassical cannabinoid agonist interaction Biopolymers 2003, 71(2):169-89. 12767117 10.1002/bip.10424
34. Bhave G Nadin BM Brasier DJ Glauner KS Shah RD Heinemann SF Karim F Gereau RW 4th Membrane topology of a metabotropic glutamate receptor J Biol Chem 2003, 278(32):30294-301. 12764131 10.1074/jbc.M303258200
35. Chambers JJ Nichols DE A homology-based model of the human 5-HT2A receptor derived from an in silico activated G-protein coupled receptor J Comput Aided Mol Des 2002, 16(7):511-20. 12510883 10.1023/ A:1021275430021
36. Stenkamp RE Filipek S Driessen CA Teller DC Palczewski K Crystal structure of rhodopsin: A template for cone visual pigments and other G protein-coupled receptors Biochim Biophys Acta 2002, 1565(2):168-82. 12409193 10.1016/S0005-2736(02)00567-9
37. Deraet M Rihakova L Boucard A Pèrodin J Sauvé S Mathieu AP Guillemette G Leduc R Lavigne P Escher E Angiotensin II is bound to both receptors AT1 and AT2, parallel to the transmembrane domains and in an extended form Can J Physiol Pharmacol 2002, 80(5):418-25. 12056548 10.1139/y02-060
38. Lopez-Rodriguez ML Murcia M Benhamu B Olivella M Campillo M Pardo L Computational model of the complex between GR113808 and the 5-HT4 receptor guided by site-directed mutagenesis and the crystal structure of rhodopsin J Comput Aided Mol Des 2001, 15(11):1025-33. 11989623 10.1023/A:1014895611874
39. Gao ZG Chen A Barak D Kim SK Müller CE Jacobson KA Identification by site-directed mutagenesis of residues involved in ligand recognition and activation of the human A3 adenosine receptor J Biol Chem 2002, 277(21):19056-63. 11891221 10.1074/jbc.M110960200
40. Zhang Y Sham YY Rajamani R Gao J Portoghese PS Homology modeling and molecular dynamics simulations of the mu opoid receptor in a membrane-aqueous system Chembiochem 2005, 6(5):853-859. 10.1208/ps020102 15776407
41. Greasley PJ Fanelli F Scheer A Abuin L Nenniger-Tosato M DeBenedetti PG Cotecchia S Mutational and computational analysis of the alpha(1b)-adrenergic receptor. Involvement of basic and hydrophobic residues in receptor activation and G protein coupling J Biol Chem 2001, 276(49):46485-94. 11585821 10.1074/jbc.M105791200
42. Nikiforovich GV Galaktionov S Balodis J Marshall GR Novel approach to computer modeling of seven-helical transmembrane proteins: Current progress in the test case of bacteriorhodopsin Acta Biochim Pol 2001, 48(1):53-64. 11440183
43. Nikiforovich GV Marshall GR 3D model for TM region of the AT-1 receptor in complex with angiotensin II independently validated by site-directed mutagenesis data Biochem Biophys Res Commun 2001, 286(5):1204-11. 11527428 10.1006/bbrc.2001.5526
44. Filipek S Teller DC Palczewski K Stenkamp R The crystallographic model of and its use in studies of other G protein-coupled receptors Annu Rev Biophys Biomol Struct 2003, 32:375-97. 12574068 10.1146/ annurev.biophys.32.110601.142520 1351250
45. Archer E Maigret B Escrieut C Pradayrol L Fourmy D Rhodopsin crystal: new template yielding realistic models of G-protein-coupled receptors? Trends Pharmacol Sci 2003, 24(1):36-40. 12498729 10.1016/ S0165-6147(02)00009-3
46. Peng JY Vaidehi N Hall SE Goddard WA 3rd The predicted 3D structures of the human M1 muscarinic acetylcholine receptor with agonist or antagonist bound Chem Med Chem 2006, 1(8):878-90. 16902941
47. Vaidehi N Schlyer S Trabanino RJ Floriano WB Abrol R Sharma S Kochanny M Koovakat S Dunning L Liang M Fox JM de Mendonça FL Pease JE Goddard WA 3rd Horuk R Predictions of CCR1 chemokine receptor structure and BX 471 antagonist binding followed by experimental validation J Biol Chem 2006, 281(37):27613-20. 16837468 10.1074/jbc.M601389200
48. Floriano WB Hall S Vaidehi N Kim U Drayna D Goddard WA 3rd Modeling the human PTC bitter-taste receptor interactions with bitter tastants J Mol Model 2006, 12(6):931-41. 16607493 10.1007/s00894-006-0102-6
49. Spijker P Vaidehi N Freddolino PL Hilbers PA Goddard WA 3rd Dynamic behavior of fully solvated beta2-adrenergic receptor, embedded in the membrane with bound agonist or antagonist Proc Natl Acad Sci USA 2006, 103(13):4882-7. 16551744 10.1073/pnas.0511329103 1458764
50. Hummel P Vaidehi N Floriano WB Hall SE Goddard WA 3rd Test of the Binding Threshold Hypothesis for olfactory receptors: Explanation of the differential binding of ketones to the mouse and human orthologs of olfactory receptor 912-93 Protein Sci 2005, 14(3):703-10. 15722446 10.1110/ps.041119705
51. Hall SE Floriano WB Vaidehi N Goddard WA 3rd Predicted 3-D structures for mouse I7 and rat I7 olfactory receptors and comparison of predicted odor recognition profiles with experiment Chem Senses 2004, 29(7):595-616. 15337685 10.1093/chemse/bjh063
52. Floriano WB Vaidehi N Goddard WA 3rd Making sense of olfaction through predictions of the 3-D structure and function of olfactory receptors Chem Senses 2004, 29(4):269-90. 15150141 10.1093/chemse/bjh030
53. Trabanino RJ Hall SE Vaidehi N Floriano WB Kam VW Goddard WA 3rd First principles predictions of the structure and function of g-protein-coupled receptors: Validation for bovine rhodopsin Biophys J 2004, 86(4):1904-21. 1304048 15041637
54. Freddolino PL Kalani MY Vaidehi N Floriano WB Hall SE Trabanino RJ Kam VW Goddard WA 3rd Predicted 3D structure for the human beta 2 adrenergic receptor and its binding site for agonists and antagonists Proc Natl Acad Sci USA 2004, 101(9):2736-41. 14981238 10.1073/pnas.0308751101 365690
55. Vaidehi N Floriano WB Trabanino R Hall SE Freddolino P Choi EJ Zamanakos G Goddard WA 3rd Prediction of structure and function of G protein-coupled receptors Proc Natl Acad Sci USA 2002, 99(20):12622-7. 12351677 10.1073/pnas.122357199 130510
56. Kinsella GK Rozas I Watson GW Comparative molecular dynamics simulations of uncomplexed, 'agonist-bound' and 'antagonist-bound' alpha1A adrenoceptor models Biochem Biophys Res Commun 2005, 333(3):737-41. 15955528 10.1016/j.bbrc.2005.05.159
57. Kinsella GK Rozas I Watson GW Computational study of antagonist/alpha1A adrenoceptor complexes - observations of conformational variations on the formation of ligand/receptor complexes J Med Chem 2006, 49(2):501-10. 16420037 10.1021/jm0503751
58. Thompson MA ArgusLab 4.0.1 ArgusLab 4.0.1 Planaria Software LLC, Seattle, WA. http://www.arguslab.com
59. Goodsell DS Morris GM Olson AJ Automated docking of flexible ligands: applications of AutoDock J Mol Recognit 1996, 9(1):1-5. 8723313 10.1002/ (SICI)1099-1352(199601)9:1<1::AID-JMR241>3.0.CO;2-6
60. Morris GA Goddsell DS Halliday RS Huey R Hart WE Belew RK Olson AJ Automated docking using a lamarckian genetic algorithm and an empirical binding free energy function J Comp Chem 1998, 19:1639-1662. 10515982 10.1002/(SICI)1096-987X(19981115)19:14<1639::AID-JCC10>3.0.CO;2-B
61. Park H Lee J Lee S Critical assessment of the automated AutoDock as a new docking tool for virtual screening Proteins 2006, 65:549-554. 16519899 10.1016/j.jmb.2006.02.008
62. Thompson JD Higgins DG Gibson TJ CLUSTAL W: Improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice Nucleic Acids Res 1994, 22(22):4673-80. 7984417 10.1093/nar/22.22.4673 308517
63. Malherbe P Kew JN Richards JG Knoflach F Kratzeisen C Zenner MT Faull RL Kemp JA Mutel V Identification and characterization of a novel splice variant of the metabotropic glutamate receptor 5 gene in human hippocampus and cerebellum Brain Res Mol Brain Res 2002, 109(1-2):168-78. 12531526 10.1016/S0169-328X(02)00557-0
64. Sali A Potterton L Yuan F van Vlijmen H Karplus M Evaluation of comparative protein modeling by MODELLER Proteins 1995, 23(3):318-26. 8710825 10.1002/prot.340230306
65. Marti-Renom MA Stuart AC Fiser A Sánchez R Melo F Sali A Comparative protein structure modeling of genes and genomes Annu Rev Biophys Biomol Struct 2000, 29:291-325. 10940251 10.1146/ annurev.biophys.29.1.291
66. Laskowski RA MacArthur MW Moss DS Thornton JM PROCHECK: A program to check the stereochemical quality of protein structures J Appl Cryst 1993, 26:283-291. 10.1107/S0021889892009944
67. Davis IW Murray LW Richardson JS Richardson DC MOLPROBITY: Structure validation and all-atom contact analysis for nucleic acids and their complexes Nucleic Acids Res 2004, 32(Web Server):W615-9. 15215462 10.1093/nar/gkh398 441536
68. Vriend G WHAT IF: A molecular modeling and drug design program J Mol Graph 1990, 8(1):-52-6, 29. 2268628 10.1016/0263-7855(90)80070-V
69. ChemDraw Software http://www.cambridgesoft.com/software/ChemDraw/
70. Knoflach F Mutel V Jolidon S Kew JN Malherbe P Vieria E Wichmann J Kemp JA Positive allosteric modulators of metabotropic glutamate 1 receptor: characterization, mechanism of action, and binding site Proc Natl Acad Sci USA 2001, 98(23):13402-7. 11606768 10.1073/pnas.231358298 60883
71. Lavreysen H Janssen C Bischoff F Langlois X Leysen JE Lesage AS [3H]R214127: A novel high-affinity radioligand for the mGlu1 receptor reveals a common binding site shared by multiple allosteric antagonists Mol Pharmacol 2003, 63(5):1082-93. 12695537 10.1124/mol.63.5.1082
72. Zheng GZ Bhatia P Daanen J Kolasa T Patel M Latshaw S El Kouhen OF Chang R Uchic ME Miller L Nakane M Lehto SG Honore MP Moreland RB Brioni JD Stewart AO Structure-activity relationship of triazafluorenone derivatives as potent and selective mGluR1 antagonists J Med Chem 2005, 48(23):7374-88. 16279797 10.1021/jm0504407
73. Kohara A Toya T Tamura S Watabiki T Nagakura Y Shitaka Y Hayashibe S Kawabata S Okada M 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 noncompetitive antagonist of metabotropic glutamate receptor type 1. J Pharmacol Exp Ther 2005, 315(1): 163-9.
74. Gasparini F Andres H Flor PJ Heinrich M Inderbitzin W Lingenhohl K Müller H Munk VC 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):407-9. 11814808 10.1016/S0960-894X(01)00767-3
75. Gasparini F Kuhn R Pin JP Allosteric modulators of group I metabotropic glutamate receptors: Novel subtype-selective ligands and therapeutic perspectives Curr Opin Pharmacol 2002, 2(1):43-9. 11786307 10.1016/ S1471-4892(01)00119-9
76. O'Brien JA Lemaire W Wittmann M Jacobson MA Ha SN Wisnoski DD Lindsley CW Schaffhauser HJ Rowe B Sur C Duggan ME Pettibone DJ Conn PJ Williams DL Jr A novel selective allosteric modulator potentiates the activity of native metabotropic glutamate receptor subtype 5 in rat forebrain J Pharmacol Exp Ther 2004, 309(2):568-77. 14747613 10.1124/jpet.103.061747
77. Porter RH Jaeschke G Spooren W Ballard TM Büttelmann B Kolczewski S Peters JU Prinssen E Wichmann J Vieria E Mühlemann A Gatti S Mutel V Malherbe P 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):711-21. 16040814 10.1124/jpet.105.089839
78. Anderson JJ Rao SP Rowe B Giracello DR Holtz G Chapman DF Tehrani L Bradbury MJ Cosford ND Varney MA [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 2002, 303(3):1044-51. 12438526 10.1124/jpet.102.040618
79. Rodriguez AL Nong Y Sekaran NK Alagille D Tamagnan GD Conn PJ 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 2005, 68(6):1793-802. 16155210
80. Pinkerton AB Vernier JM Schaffhauser H Rowe BA Campbell UC Rodriguez DE Lorrain DS Baccei CS Daggett LP Bristow LJ Phenyl-tetrazolyl acetophenones: Discovery of positive allosteric potentiatiors for the metabotropic glutamate 2 receptor J Med Chem 2004, 47(18):4595-9. 15317469 10.1021/jm040088h
81. 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 PJ (-)-PHCCC, a positive allosteric modulator of mGluR4: Characterization, mechanism of action, and neuroprotection Neuropharmacology 2003, 45(7):895-906. 14573382 10.1016/S0028-3908(03)00271-5
82. Mitsukawa K Yamamoto R Ofner S Nozulak J Pescott O Lukic S Stoehr N Mombereau C Kuhn R McAllister KH van der Putten H Cryan JF Flor PJ 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 2005, 102(51):18712-7. 16339898 10.1073/ pnas.0508063102 1317946
83. Pymol software http://www.pymol.org