Chemical biology of mglu4 receptor activation: Dogmas, challenges, strategies and opportunities

Current Topics in Medicinal Chemistry

Volumn 14, Issue 15, 2014, Pages 1755-1770

  Huang, Xinyan ^a   Dale, Elena ^b   Brodbeck, Robbin M ^a   Doller, Dario ^c  

^a Molecular Pharmacology SAR Neuroinflammation Disease Biology Unit   (United States)

^b Bioanalysis Physiology   (United States)

^c LUNDBECK RESEARCH USA   (United States)

Author keywords

Allosteric ligand; Heterodimer; MGlu4 receptor; Orthosteric ligand; Positive allosteric modulator

Indexed keywords

AMPA RECEPTOR; CARBON 11; G PROTEIN COUPLED INWARDLY RECTIFYING POTASSIUM CHANNEL; G PROTEIN COUPLED RECEPTOR; GLUTAMIC ACID; HETERODIMER; IONOTROPIC RECEPTOR; LEUCINE RICH REPEAT KINASE 2; METABOTROPIC RECEPTOR 1; METABOTROPIC RECEPTOR 2; METABOTROPIC RECEPTOR 3; METABOTROPIC RECEPTOR 4; METABOTROPIC RECEPTOR 5; METABOTROPIC RECEPTOR 6; METABOTROPIC RECEPTOR 7; METABOTROPIC RECEPTOR 8; METABOTROPIC RECEPTOR AGONIST; MITOGEN ACTIVATED PROTEIN KINASE; N METHYL DEXTRO ASPARTIC ACID RECEPTOR; PERTUSSIS TOXIN; PHOSPHATIDYLINOSITOL 3 KINASE; RADIOLIGAND; VOLTAGE GATED CALCIUM CHANNEL; ION CHANNEL; LIGAND; METABOTROPIC RECEPTOR; MOLECULAR LIBRARY; RADIOPHARMACEUTICAL AGENT;

ALLOSTERISM; ANXIETY; ARTICLE; BINDING AFFINITY; BLOOD BRAIN BARRIER; CALCIUM MOBILIZATION; CENTRAL NERVOUS SYSTEM; CHEMICAL STRUCTURE; DRUG DESIGN; DRUG MECHANISM; EPILEPSY; EXCITATORY POSTSYNAPTIC POTENTIAL; GENETIC POLYMORPHISM; HUMAN; INTRACELLULAR SIGNALING; ISCHEMIA; MEMBRANE PERMEABILITY; MULTIPLE SCLEROSIS; NEOPLASM; NEUROPATHIC PAIN; NEUROPROTECTION; NONHUMAN; PARKINSON DISEASE; PROTEIN LOCALIZATION; QUANTITATIVE STRUCTURE ACTIVITY RELATION; RECEPTOR DOWN REGULATION; SCHIZOPHRENIA; SYNAPTIC TRANSMISSION; AGONISTS; BINDING SITE; CHEMISTRY; DEGENERATIVE DISEASE; GENE EXPRESSION REGULATION; GENETICS; METABOLISM; MOLECULAR LIBRARY; PATHOLOGY; PHARMACOLOGY; PROTEIN MULTIMERIZATION; SIGNAL TRANSDUCTION; STRUCTURE ACTIVITY RELATION; SYNTHESIS; TRANSPORT AT THE CELLULAR LEVEL;

ALLOSTERIC REGULATION; ALLOSTERIC SITE; BIOLOGICAL TRANSPORT; CENTRAL NERVOUS SYSTEM; DRUG DESIGN; GENE EXPRESSION REGULATION; HUMANS; ION CHANNELS; LIGANDS; MITOGEN-ACTIVATED PROTEIN KINASES; NEURODEGENERATIVE DISEASES; PROTEIN MULTIMERIZATION; RADIOPHARMACEUTICALS; RECEPTORS, METABOTROPIC GLUTAMATE; SIGNAL TRANSDUCTION; SMALL MOLECULE LIBRARIES; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84925937537     PISSN: 15680266     EISSN: 18734294     Source Type: Journal    
DOI: 10.2174/1568026614666140902143830     Document Type: Article

References (108)

1. Lindsley, C. W.; Hopkins, C. R. Metabotropic glutamate receptor 4 (mGlu4)-positive allosteric modulators for the treatment of Parkinson's disease: historical perspective and review of the patent literature. Expert Opin. Ther. Pat., 2012, 22 (5), 461-81;
2. Celanire, S.; Campo, B., Recent advances in the drug discovery of metabotropic glutamate receptor 4 (mGluR4) activators for the treatment of CNS and non-CNS disorders. Expert. Opin Drug Discov., 2012, 7 (3), 261-80;
3. Flor, P. J.; Acher, F. C. Orthosteric versus allosteric GPCR activation: the great challenge of group-III mGluRs. Biochem. Pharmacol., 2012, 84 (4), 414-24;
4. Duty, S. Targeting glutamate receptors to tackle the pathogenesis, clinical symptoms and levodopa-induced dyskinesia associated with Parkinson's disease. CNS Drugs, 2012, 26 (12), 1017-32;
5. Robichaud, A. J.; Engers, D. W.; Lindsley, C. W.; Hopkins, C. R. Recent progress on the identification of metabotropic glutamate 4 receptor ligands and their potential utility as CNS therapeutics. ACS Chem. Neurosci., 2011, 2 (8), 433-49.
6. Lopez, S.; Turle-Lorenzo, N.; Acher, F.; De Leonibus, E.; Mele, A.; Amalric, M. Targeting group III metabotropic glutamate receptors produces complex behavioral effects in rodent models of Parkinson's disease. Neurosci: Neurosci., 2007, 27 (25), 6701-11;
7. Austin, P. J.; Betts, M. J.; Broadstock, M.; O'Neill, M. J.; Mitchell, S. N.; Duty, S. Symptomatic and neuroprotective effects following activation of nigral group III metabotropic glutamate receptors in rodent models of Parkinson's disease. Br. J. Pharmacol., 2010, 160 (7), 1741-1753;
8. Cuomo, D.; Martella, G.; Barabino, E.; Platania, P.; Vita, D.; Madeo, G.; Selvam, C.; Goudet, C.; Oueslati, N.; Pin, J.-P.; Acher, F.; Pisani, A.; Beurrier, C.; Melon, C.; Kerkerian-Le Goff, L.; Gubellini, P. Metabotropic glutamate receptor subtype 4 selectively modulates both glutamate and GABA transmission in the striatum: implications for Parkinson’s disease treatment. J Neuroche., 2009, 109 (4), 1096-1105;
9. Goudet, C.; Vilar, B.; Courtiol, T.; Deltheil, T.; Bessiron, T.; Brabet, I.; Oueslati, N.; Rigault, D.; Bertrand, H. O.; McLean, H.; Daniel, H.; Amalric, M.; Acher, F.; Pin, J. P. A novel selective metabotropic glutamate receptor 4 agonist reveals new possibilities for developing subtype selective ligands with therapeutic potential. FASEB 2012, 26 (4), 1682-93;
10. Bennouar, K.-E.; Uberti, M. A.; Melon, C.; Bacolod, M. D.; Jimenez, H. N.; Cajina, M.; Kerkerian-Le Goff, L.; Doller, D.; Gubellini, P. Synergy between l-DOPA and a novel positive allosteric modulator of metabotropic glutamate receptor 4: Implications for Parkinson's disease treatment and dyskinesia. Neuropharmacology, 2013, 66 (0), 158-169;
11. Konieczny, J.; Wardas, J.; Kuter, K.; Pilc, A.; Ossowska, K. The influence of group III metabotropic glutamate receptor stimulation by (1S,3R,4S)-1-aminocyclo-pentane-1,3,4-tricarboxylic acid on the parkinsonian-like akinesia and striatal proenkephalin and prodynorphin mRNA expression in rats. Neuroscience, 2007, 145 (2), 611-20;
12. MacInnes, N.; Messenger, M. J.; Duty, S. Activation of group III metabotropic glutamate receptors in selected regions of the basal ganglia alleviates akinesia in the reserpine-treated rat. Br. J. Pharmacol., 2004, 141 (1), 15-22;
13. Jones, C. K.; Bubser, M.; Thompson, A. D.; Dickerson, J. W.; Turle-Lorenzo, N.; Amalric, M.; Blobaum, A. L.; Bridges, T. M.; Morrison, R. D.; Jadhav, S.; Engers, D. W.; Italiano, K.; Bode, J.; Daniels, J. S.; Lindsley, C. W.; Hopkins, C. R.; Conn, P. J.; Niswender, C. M. 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 Pharmac Exp Therapeut., 2012, 340 (2), 404-21;
14. Le Poul, E.; Bolea, C.; Girard, F.; Poli, S.; Charvin, D.; Campo, B.; Bortoli, J.; Bessif, A.; Luo, B.; Koser, A. J.; Hodge, L. M.; Smith, K. M.; DiLella, A. G.; Liverton, N.; Hess, F.; Browne, S. E.; Reynolds, I. J. A potent and selective metabotropic glutamate receptor 4 positive allosteric modulator improves movement in rodent models of Parkinson's disease. J Pharma Exp. Therapeut., 2012, 343 (1), 167-77.
15. Goudet, C.; Chapuy, E.; Alloui, A.; Acher, F.; Pin, J. P.; Eschalier, A., Group III metabotropic glutamate receptors inhibit hyperalgesia in animal models of inflammation and neuropathic pain. Pain, 2008, 137 (1), 112-24;
16. Vilar, B.; Busserolles, J.; Ling, B.; Laffray, S.; Ulmann, L.; Malhaire, F.; Chapuy, E.; Aissouni, Y.; Etienne, M.; Bourinet, E.; Acher, F.; Pin, J.-P.; Eschalier, A.; Goudet, C., Alleviating Pain Hypersensitivity through Activation of Type 4 Metabotropic Glutamate Receptor. J of Neurosci., 2013, 33 (48), 18951-18965;
17. Wang, H.; Jiang, W.; Yang, R.; Li, Y. Spinal metabotropic glutamate receptor 4 is involved in neuropathic pain. Neuroreport, 2011, 22 (5), 244-8.
18. Ngomba, R. T.; Ferraguti, F.; Badura, A.; Citraro, R.; Santolini, I.; Battaglia, G.; Bruno, V.; De Sarro, G.; Simonyi, A.; van Luijtelaar, G.; Nicoletti, F., Positive allosteric modulation of metabotropic glutamate 4 (mGlu4) receptors enhances spontaneous and evoked absence seizures. Neuropharmacology, 2008, 54 (2), 344-54;
19. Watanabe, Y.; Kaida, Y.; Fukuhara, S.; Takechi, K.; Uehara, T.; Kamei, C., Participation of metabotropic glutamate receptors in pentetrazol-induced kindled seizure. Epilepsia, 2011, 52 (1), 140-50;
20. Yip, P. K.; Meldrum, B. S.; Rattray, M., Elevated levels of group-III metabotropic glutamate receptors in the inferior colliculus of genetically epilepsy-prone rats following intracollicular administration of L-serine-O-phosphate. J. Neurochem, 2001, 78 (1), 13-23;
21. Pitsch, J.; Schoch, S.; Gueler, N.; Flor, P. J.; van der Putten, H.; Becker, A. J., Functional role of mGluR1 and mGluR4 in pilocarpine-induced temporal lobe epilepsy. Neurobio Dis., 2007, 26 (3), 623-33.
22. Sawiska, A.; Wiero_ska, J. M.; Stachowicz, K.; Pa_ucha-Poniewiera, A.; Uberti, M. A.; Bacolod, M. A.; Doller, D.; Pilc, A., Anxiolytic-but not antidepressant-like activity of Lu AF21934, a novel, selective positive allosteric modulator of the mGlu4 receptor. Neuropharmacology, 2013, 66 (0), 225-235;
23. Wiero_ska, J. M.; Stachowicz, K.; Pa_ucha-Poniewiera, A.; Acher, F.; Bra_ski, P.; Pilc, A., Metabotropic glutamate receptor 4 novel agonist LSP1-2111 with anxiolytic, but not antidepressant-like activity, mediated by serotonergic and GABAergic systems. Neuropharmacology, 2010, 59 (7–8), 627-634.
24. Fallarino, F.; Volpi, C.; Fazio, F.; Notartomaso, S.; Vacca, C.; Busceti, C.; Bicciato, S.; Battaglia, G.; Bruno, V.; Puccetti, P.; Fioretti, M. C.; Nicoletti, F.; Grohmann, U.; Di Marco, R., Metabotropic glutamate receptor-4 modulates adaptive immunity and restrains neuroinflammation. Nat. Med., 2010, 16 (8), 897-902;
25. Taylor, D. L.; Diemel, L. T.; Pocock, J. M., Activation of Microglial Group III Metabotropic Glutamate Receptors Protects Neurons against Microglial Neurotoxicity. J.Neurosci., 2003, 23 (6), 2150-2160.
26. Wieroska, J.; Stachowicz, K.; Acher, F.; Lech, T.; Pilc, A., Opposing efficacy of group III mGlu receptor activators, LSP1-2111 and AMN082, in animal models of positive symptoms of schizophrenia. Psychopharmacology, 2012, 220 (3), 481-494.
27. Moyanova, S. G.; Mastroiacovo, F.; Kortenska, L. V.; Mitreva, R. G.; Fardone, E.; Santolini, I.; Sobrado, M.; Battaglia, G.; Bruno, V.; Nicoletti, F.; Ngomba, R. T., Protective role for type 4 metabotropic glutamate receptors against ischemic brain damage. J. Cereb. Blood Flow Metabol., 2011, 31 (4), 1107-18.
28. Iacovelli, L.; Arcella, A.; Battaglia, G.; Pazzaglia, S.; Aronica, E.; Spinsanti, P.; Caruso, A.; De Smaele, E.; Saran, A.; Gulino, A.; D'Onofrio, M.; Giangaspero, F.; Nicoletti, F., Pharmacological activation of mGlu4 metabotropic glutamate receptors inhibits the growth of medulloblastomas. J. Neurosci.,: 2006, 26 (32), 8388-97;
29. Brocke, K. S.; Staufner, C.; Luksch, H.; Geiger, K. D.; Stepulak, A.; Marzahn, J.; Schackert, G.; Temme, A.; Ikonomidou, C., Glutamate receptors in pediatric tumors of the central nervous system. Cancer biology & therapy 2010, 9 (6), 455-68;
30. Pissimissis, N.; Papageorgiou, E.; Lembessis, P.; Armakolas, A.; Koutsilieris, M., The glutamatergic system expression in human PC-3 and LNCaP prostate cancer cells. Anticancer Res., 2009, 29 (1), 371-7.
31. Pin, J.-P.; Galvez, T.; Prézeau, L., Evolution, structure, and activation mechanism of family 3/C G-protein-coupled receptors. Pharma Therapeu., 2003, 98 (3), 325-354.
32. Kammermeier, P. J., Functional and Pharmacological Characteristics of Metabotropic Glutamate Receptors 2/4 Heterodimers. Mol.Pharmac., 2012, 82 (3), 438-447;
33. Yin, S.; Noetzel, M. J.; Johnson, K. A.; Zamorano, R.; Jalan-Sakrikar, N.; Gregory, K. J.; Conn, P. J.; Niswender, C. M., Selective actions of novel allosteric modulators reveal functional heteromers of metabotropic glutamate receptors in the CNS. J. Neurosci., 2014, 34 (1), 79-94;
34. Doumazane, E.; Scholler, P.; Zwier, J. M.; Trinquet, E.; Rondard, P.; Pin, J.-P., A new approach to analyze cell surface protein complexes reveals specific heterodimeric metabotropic glutamate receptors. FASEB, 2011, 25 (1), 66-77.
35. Iacovelli, L.; Bruno, V.; Salvatore, L.; Melchiorri, D.; Gradini, R.; Caricasole, A.; Barletta, E.; De Blasi, A.; Nicoletti, F., Native group-III metabotropic glutamate receptors are coupled to the mitogen-activated protein kinase/phosphatidylinositol-3-kinase pathways. J. Neurochem., 2002, 82 (2), 216-223;
36. Iacovelli, L.; Capobianco, L.; Iula, M.; Di Giorgi Gerevini, V.; Picascia, A.; Blahos, J.; Melchiorri, D.; Nicoletti, F.; De Blasi, A., Regulation of mGlu4 Metabotropic Glutamate Receptor Signaling by Type-2 GProtein Coupled Receptor Kinase (GRK2). Mole Pharma., 2004, 65 (5), 1103-1110.
37. Yin, S.; Zamorano, R.; Conn, P. J.; Niswender, C. M., Functional selectivity induced by mGlu4 receptor positive allosteric modulation and concomitant activation of Gq coupled receptors. Neuropharmacology, 2013, 66 (0), 122-132.
38. Cartmell, J.; Schoepp, D. D., Regulation of Neurotransmitter Release by Metabotropic Glutamate Receptors. Journal of Neurochemistry 2000, 75 (3), 889-907;
39. Schoepp, D. D., Unveiling the Functions of Presynaptic Metabotropic Glutamate Receptors in the Central Nervous System. J. Pharm. Exper. Therapeu., 2001, 299 (1), 12-20.
40. Cain, S. M.; Meadows, H. J.; Dunlop, J.; Bushell, T. J., mGlu4 potentiation of K2P2.1 is dependant on C-terminal dephosphorylation. Mol. Cell Neurosci., 2008, 37 (1), 32-39.
41. Niswender, C. M.; Johnson, K. A.; Luo, Q.; Ayala, J. E.; Kim, C.; Conn, P. J.; Weaver, C. D., A Novel Assay of Gi/o-Linked G Protein-Coupled Receptor Coupling to Potassium Channels Provides New Insights into the Pharmacology of the Group III Metabotropic Glutamate Receptors. Mol. Pharmacol., 2008, 73 (4), 1213-1224;
42. Saugstad, J. A.; Segerson, T. P.; Westbrook, G. L., Metabotropic Glutamate Receptors Activate G-Protein-Coupled Inwardly Rectifying Potassium Channels in Xenopus Oocytes. J. Neurosci., 1996, 16 (19), 5979-5985.
43. Abitbol, K.; McLean, H.; Bessiron, T.; Daniel, H., A new signalling pathway for parallel fibre presynaptic type 4 metabotropic glutamate receptors (mGluR4) in the rat cerebellar cortex. J. Physiolo., 2012, 590 (13), 2977-2994.
44. Antflick, J. E.; Hampson, D. R., Modulation of glutamate release from parallel fibers by mGlu4 and pre-synaptic GABAA receptors. J Neurochem., 2012, 120 (4), 552-563.
45. Liggett, S. B., Phosphorylation Barcoding as a Mechanism of Directing GPCR Signaling. Sci. Signal., 2011, 4 (185), pe36.
46. Mathiesen, J. M.; Ramirez, M. T., The metabotropic glutamate receptor 4 is internalized and desensitized upon protein kinase C activation. Bri. J Pharmaco, 2006, 148 (3), 279-290.
47. Flor, P. J.; Lukic, S.; Rüegg, D.; Leonhardt, T.; Knöpfel, T.; Kühn, R., Molecular cloning, functional expression and pharmacological characterization of the human metabotropic glutamate receptor type 4. Neuropharmacology,1995, 34 (2), 149-155;
48. Kil, K.-E.; Zhang, Z.; Jokivarsi, K.; Gong, C.; Choi, J.-K.; Kura, S.; Brownell, A.-L., Radiosynthesis of N-(4-chloro-3-[11C]methoxyphenyl)-2-picolinamide ([11C]ML128) as a PET radiotracer for metabotropic glutamate receptor subtype 4 (mGlu4). Bioorganic Med Chem., 2013, 21 (19), 5955-5962;
49. Kinoshita, A.; Ohishi, H.; Nomura, S.; Shigemoto, R.; Nakanishi, S.; Mizuno, N., Presynaptic localization of a metabotropic glutamate receptor, mGluR4a, in the cerebellar cortex: a light and electron microscope study in the rat. Neuroscie lett., 1996, 207 (3), 199-202;
50. Makoff, A.; Lelchuk, R.; Oxer, M.; Harrington, K.; Emson, P., Molecular characterization and localization of human metabotropic glutamate receptor type 4. Mol Brain Res., 1996, 37 (1–2), 239-248;
51. Bogenpohl, J.; Galvan, A.; Hu, X.; Wichmann, T.; Smith, Y., Metabotropic glutamate receptor 4 in the basal ganglia of parkinsonian monkeys: Ultrastructural localization and electrophysiological effects of activation in the striatopallidal complex. Neuropharmacology, 2013, 66, 242-252.
52. Corti, C.; Aldegheri, L.; Somogyi, P.; Ferraguti, F., Distribution and synaptic localisation of the metabotropic glutamate receptor 4 (mGluR4) in the rodent CNS. Neuroscience, 2002, 110 (3), 403-420;
53. Ohishi, H.; Akazawa, C.; Shigemoto, R.; Nakanishi, S.; Mizuno, N., Distributions of the mRNAs for L-2-amino-4-phosphonobutyrate-sensitive metabotropic glutamate receptors, mGluR4 and mGluR7, in the rat brain. J. Comp. Neuro., 1995, 360 (4), 555-570.
54. Besong, G.; Battaglia, G.; D'Onofrio, M.; Di Marco, R.; Ngomba, R. T.; Storto, M.; Castiglione, M.; Mangano, K.; Busceti, C. L.; Nicoletti, F. R.; Bacon, K.; Tusche, M.; Valenti, O.; Conn, P. J.; Bruno, V.; Nicoletti, F., Activation of Group III Metabotropic Glutamate Receptors Inhibits the Production of RANTES in Glial Cell Cultures. J. Neurosci., 2002, 22 (13), 5403-5411.
55. Chang, H. J.; Yoo, B. C.; Lim, S.-B.; Jeong, S.-Y.; Kim, W. H.; Park, J.-G., Metabotropic Glutamate Receptor 4 Expression in Colorectal Carcinoma and Its Prognostic Significance. Clin. Cancer Res., 2005, 11 (9), 3288-3295.
56. Toyono, T.; Seta, Y.; Kataoka, S.; Harada, H.; Morotomi, T.; Kawano, S.; Shigemoto, R.; Toyoshima, K., Expression of the Metabotropic Glutamate Receptor, mGluR4a, in the Taste Hairs of Taste Buds in Rat Gustatory Papillae. Arch. Histo. Cytol., 2002, 65, (1), 91-96.
57. Uehara, S.; Muroyama, A.; Echigo, N.; Morimoto, R.; Otsuka, M.; Yatsushiro, S.; Moriyama, Y., Metabotropic Glutamate Receptor Type 4 Is Involved in Autoinhibitory Cascade for Glucagon Secretion by _-Cells of Islet of Langerhans. Diabetes, 2004, 53 (4), 998-1006.
58. Hinoi, E.; Fujimori, S.; Nakamura, Y.; Yoneda, Y., Group III Metabotropic Glutamate Receptors in Rat Cultured Calvarial Osteoblasts. Biochem. Biophy. Res. Commu., 2001, 281 (2), 341-346.
59. Cappuccio, I.; Verani, R.; Spinsanti, P.; Niccolini, C.; Gradini, R.; Costantino, S.; Nicoletti, F.; Melchiorri, D., Context-dependent regulation of embryonic stem cell differentiation by mGlu4 metabotropic glutamate receptors. Neuropharmacology, 2006, 51 (3), 606-611;
60. Canudas, A. M.; Di Giorgi-Gerevini, V.; Iacovelli, L.; Nano, G.; D'Onofrio, M.; Arcella, A.; Giangaspero, F.; Busceti, C.; Ricci-Vitiani, L.; Battaglia, G.; Nicoletti, F.; Melchiorri, D., PHCCC, a Specific Enhancer of Type 4 Metabotropic Glutamate Receptors, Reduces Proliferation and Promotes Differentiation of Cerebellar Granule Cell Neuroprecursors. J Neurosci., 2004, 24 (46), 10343-10352.
61. Fallin, M. D.; Lasseter, V. K.; Avramopoulos, D.; Nicodemus, K. K.; Wolyniec, P. S.; McGrath, J. A.; Steel, G.; Nestadt, G.; Liang, K. Y.; Huganir, R. L.; Valle, D.; Pulver, A. E., Bipolar I disorder and schizophrenia: a 440-single-nucleotide polymorphism screen of 64 candidate genes among Ashkenazi Jewish case-parent trios. Am. J. Hum. Genet., 2005, 77 (6), 918-36.
62. Shibata, H.; Tani, A.; Chikuhara, T.; Kikuta, R.; Sakai, M.; Ninomiya, H.; Tashiro, N.; Iwata, N.; Ozaki, N.; Fukumaki, Y., Association study of polymorphisms in the group III metabotropic glutamate receptor genes, GRM4 and GRM7, with schizophrenia. Psychiatry. Res., 2009, 167 (1-2), 88-96.
63. Gandhi, S.; Wood, N. W., Genome-wide association studies: the key to unlocking neurodegeneration? Nat. Neurosci., 2010, 13 (7), 789-94.
64. MacArthur, L.; Ressom, H.; Shah, S.; Federoff, H. J., Network modeling to identify new mechanisms and therapeutic targets for Parkinson's disease. Expert Rev. Neurother, 2013, 13 (6), 685-93.
65. Savage, S. A.; Mirabello, L.; Wang, Z.; Gastier-Foster, J. M.; Gorlick, R.; Khanna, C.; Flanagan, A. M.; Tirabosco, R.; Andrulis, I. L.; Wunder, J. S.; Gokgoz, N.; Patino-Garcia, A.; Sierrasesumaga, L.; Lecanda, F.; Kurucu, N.; Ilhan, I. E.; Sari, N.; Serra, M.; Hattinger, C.; Picci, P.; Spector, L. G.; Barkauskas, D. A.; Marina, N.; de Toledo, S. R.; Petrilli, A. S.; Amary, M. F.; Halai, D.; Thomas, D. M.; Douglass, C.; Meltzer, P. S.; Jacobs, K.; Chung, C. C.; Berndt, S. I.; Purdue, M. P.; Caporaso, N. E.; Tucker, M.; Rothman, N.; Landi, M. T.; Silverman, D. T.; Kraft, P.; Hunter, D. J.; Malats, N.; Kogevinas, M.; Wacholder, S.; Troisi, R.; Helman, L.; Fraumeni, J. F., Jr.; Yeager, M.; Hoover, R. N.; Chanock, S. J., Genome-wide association study identifies two susceptibility loci for osteosarcoma. Nat. Genet., 2013, 45 (7), 799-803.
66. Antflick, J. E.; Vetiska, S.; Baizer, J. S.; Yao, Y.; Baker, G. B.; Hampson, D. R., L-Serine-O-phosphate in the central nervous system. Brain Res., 2009, 1300, 1-13.
67. Fazio, F.; Lionetto, L.; Molinaro, G.; Bertrand, H. O.; Acher, F.; Ngomba, R. T.; Notartomaso, S.; Curini, M.; Rosati, O.; Scarselli, P.; Di Marco, R.; Battaglia, G.; Bruno, V.; Simmaco, M.; Pin, J. P.; Nicoletti, F.; Goudet, C., Cinnabarinic acid, an endogenous metabolite of the kynurenine pathway, activates type 4 metabotropic glutamate receptors. Mol. Pharmacol., 2012, 81 (5), 643-56.
68. Bunnage, M. E.; Chekler, E. L.; Jones, L. H., Target validation using chemical probes. Nat. Chem. Biol., 2013, 9 (4), 195-9.
69. Di, L.; Rong, H.; Feng, B., Demystifying brain penetration in central nervous system drug discovery. Miniperspective. J. Med. Chem., 2013, 56 (1), 2-12.
70. Pajouhesh, H.; Lenz, G. R., Medicinal chemical properties of successful central nervous system drugs. NeuroRx, 2005, 2 (4), 541-53.
71. Smith, D. A.; Di, L.; Kerns, E. H., The effect of plasma protein binding on in vivo efficacy: misconceptions in drug discovery. Nature reviews. Drug Discov., 2010, 9 (12), 929-39.
72. Mariappan, T. T.; Mandlekar, S.; Marathe, P., Insight into tissue unbound concentration: utility in drug discovery and development. Curr. Drug Metabo., 2013, 14 (3), 324-40.
73. Cajina, M.; Nattini, M.; Song, D.; Smagin, G.; Jørgensen, E. B.; Chandrasena, G.; Bundgaard, C.; Toft, D. B.; Huang, X.; Acher, F.; Doller, D., Qualification of LSP1-2111 as a Brain Penetrant Group III Metabotropic Glutamate Receptor Orthosteric Agonist. ACS Med. Chem. Lett., 2013, 5, 119-23.
74. Imre, G., The preclinical properties of a novel group II metabotropic glutamate receptor agonist LY379268. CNS Drug Reviews., 2007, 13 (4), 444-64.
75. Begley, D. J., Delivery of therapeutic agents to the central nervous system: the problems and the possibilities. Pharmacol., Ther., 2004, 104 (1), 29-45.
76. Utley, T.; Haddenham, D.; Salovich, J. M.; Zamorano, R.; Vinson, P. N.; Lindsley, C. W.; Hopkins, C. R.; Niswender, C. M., Synthesis and SAR of a novel metabotropic glutamate receptor 4 (mGlu4) antagonist: unexpected 'molecular switch' from a closely related mGlu4 positive allosteric modulator. Bioorg. Med. Chem. Lett., 2011, 21 (23), 6955-9.
77. Wood, M. R.; Hopkins, C. R.; Brogan, J. T.; Conn, P. J.; Lindsley, C. W., "Molecular switches" on mGluR allosteric ligands that modulate modes of pharmacology. Biochemistry, 2011, 50 (13), 2403-10.
78. Christov, C.; Gonzalez-Bulnes, P.; Malhaire, F.; Karabencheva, T.; Goudet, C.; Pin, J. P.; Llebaria, A.; Giraldo, J., Integrated synthetic, pharmacological, and computational investigation of cis-2-(3,5-dichlorophenylcarbamoyl)cyclohexanecarboxylic acid enantiomers as positive allosteric modulators of metabotropic glutamate receptor subtype 4. ChemMedChem., 2011, 6 (1), 131-40.
79. Wenthur, C. J.; Gentry, P. R.; Mathews, T. P.; Lindsley, C. W., Drugs for allosteric sites on receptors. Annu. Rev. Pharmacol. Toxicol. 2014, 54, 165-84;
80. Burford, N. T.; Traynor, J. R.; Alt, A., Positive Allosteric Modulators of the mu-Opioid Receptor: A Novel Approach for Future Pain Medications. Br. J. Pharmacol., 2014.
81. Hudson, B. D.; Ulven, T.; Milligan, G., The therapeutic potential of allosteric ligands for free fatty acid sensitive GPCRs. Curr. Top. Med. Chem., 2013, 13 (1), 14-25;
82. Urwyler, S., Allosteric modulation of family C G-protein-coupled receptors: from molecular insights to therapeutic perspectives. Pharmacol. Rev., 2011, 63 (1), 59-126.
83. Melancon, B. J.; Hopkins, C. R.; Wood, M. R.; Emmitte, K. A.; Niswender, C. M.; Christopoulos, A.; Conn, P. J.; Lindsley, C. W., Allosteric modulation of seven transmembrane spanning receptors: theory, practice, and opportunities for central nervous system drug discovery. J. Med. Chem., 2012, 55 (4), 1445-64.
84. Langmead, C. J.; Christopoulos, A., Supra-physiological efficacy at GPCRs: superstition or super agonists? Br. J. Pharmacol., 2013, 169 (2), 353-6.
85. Knudsen, L. B.; Hastrup, S.; Underwood, C. R.; Wulff, B. S.; Fleckner, J., Functional importance of GLP-1 receptor species and expression levels in cell lines. Regul. Pept., 2012, 175 (1-3), 21-9;
86. Noetzel, M. J.; Rook, J. M.; Vinson, P. N.; Cho, H. P.; Days, E.; Zhou, Y.; Rodriguez, A. L.; Lavreysen, H.; Stauffer, S. R.; Niswender, C. M.; Xiang, Z.; Daniels, J. S.; Jones, C. K.; Lindsley, C. W.; Weaver, C. D.; Conn, P. J., 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., 2012, 81 (2), 120-33.
87. Niswender, C. M.; Johnson, K. A.; Weaver, C. D.; Jones, C. K.; Xiang, Z.; Luo, Q.; Rodriguez, A. L.; Marlo, J. E.; de Paulis, T.; Thompson, A. D.; Days, E. L.; Nalywajko, T.; Austin, C. A.; Williams, M. B.; Ayala, J. E.; Williams, R.; Lindsley, C. W.; Conn, P. J., Discovery, characterization, and antiparkinsonian effect of novel positive allosteric modulators of metabotropic glutamate receptor 4. Mol. Pharmacol., 2008, 74 (5), 1345-58.
88. Williams, R.; Johnson, K. A.; Gentry, P. R.; Niswender, C. M.; Weaver, C. D.; Conn, P. J.; Lindsley, C. W.; Hopkins, C. R., Synthesis and SAR of a novel positive allosteric modulator (PAM) of the metabotropic glutamate receptor 4 (mGluR4). Bioorg. Med. Chem. Lett., 2009, 19 (17), 4967-70.
89. Duan, Z.; Zhang, X.; Zhu, G. X.; Gao, Y.; Xue, X., Activation of mGluR4 promotes proliferation of rat neural progenitor cells while mediating activation of ERK1/2 signaling pathway. Cell. Mol. Biol. (Noisy-le-grand), 2013, 59 Suppl, OL1809-17;
90. Klakotskaia, D.; Ramsey, A. K.; Fowler, S. W.; Serfozo, P.; Simonyi, A.; Schachtman, T. R., Effects of group II and III metabotropic glutamate receptor ligands on conditioned taste aversion learning. Behav. Brain Res., 2013, 253, 9-16;
91. Wang, W. Y.; Wang, H.; Luo, Y.; Jia, L. J.; Zhao, J. N.; Zhang, H. H.; Ma, Z. W.; Xue, Q. S.; Yu, B. W., The effects of metabotropic glutamate receptor 7 allosteric agonist N,N'-dibenzhydrylethane-1,2-diamine dihydrochloride on developmental sevoflurane neurotoxicity: role of extracellular signal-regulated kinase 1 and 2 mitogen-activated protein kinase signaling pathway. Neuroscience, 2012, 205, 167-77;
92. Davis, M. J.; Haley, T.; Duvoisin, R. M.; Raber, J., Measures of anxiety, sensorimotor function, and memory in male and female mGluR4(-)/(-) mice. Behav. Brain Res, 2012, 229 (1), 21-8;
93. Vernon, A. C.; Smith, E. J.; Stevanato, L.; Modo, M., Selective activation of metabotropic glutamate receptor 7 induces inhibition of cellular proliferation and promotes astrocyte differentiation of ventral mesencephalon human neural stem/progenitor cells. Neurochem. Int., 2011, 59 (3), 421-31.
94. Rossi, F.; Marabese, I.; De Chiaro, M.; Boccella, S.; Luongo, L.; Guida, F.; De Gregorio, D.; Giordano, C.; de Novellis, V.; Palazzo, E.; Maione, S., Dorsal striatum metabotropic glutamate receptor 8 affects nocifensive responses and rostral ventromedial medulla cell activity in neuropathic pain conditions. J. Neurophysiol., 2013;
95. Guimaraes-Souza, E. M.; Calaza, K. C., Selective activation of group III metabotropic glutamate receptor subtypes produces different patterns of gamma-aminobutyric acid immunoreactivity and glutamate release in the retina. J. Neurosci. Res. 2012, 90 (12), 2349-61;
96. Bogenpohl, J.; Galvan, A.; Hu, X.; Wichmann, T.; Smith, Y., Metabotropic glutamate receptor 4 in the basal ganglia of parkinsonian monkeys: ultrastructural localization and electrophysiological effects of activation in the striatopallidal complex. Neuropharmacology,2013, 66, 242-52;
97. Betts, M. J.; O'Neill, M. J.; Duty, S., Allosteric modulation of the group III mGlu(4) receptor provides functional neuroprotection in the 6-hydroxydopamine rat model of Parkinson's disease. Br. J. Pharmacol., 2012, 166 (8), 2317-30.
98. Macek, T. A.; Winder, D. G.; Gereau, R. W. t.; Ladd, C. O.; Conn, P. J., Differential involvement of group II and group III mGluRs as autoreceptors at lateral and medial perforant path synapses. J. Neurophysiol., 1996, 76 (6), 3798-806.
99. Ferre, S.; Casado, V.; Devi, L. A.; Filizola, M.; Jockers, R.; Lohse, M. J.; Milligan, G.; Pin, J. P.; Guitart, X., G protein-coupled receptor oligomerization revisited: functional and pharmacological perspectives. Pharmacol. Rev., 2014, 66 (2), 413-34.
100. Bennouar, K. E.; Uberti, M. A.; Melon, C.; Bacolod, M. D.; Jimenez, H. N.; Cajina, M.; Kerkerian-Le Goff, L.; Doller, D.; Gubellini, P., Synergy between L-DOPA and a novel positive allosteric modulator of metabotropic glutamate receptor 4: implications for Parkinson's disease treatment and dyskinesia. Neuropharmacology, 2013, 66, 158-69.
101. Rozenfeld, R.; Devi, L. A., Exploring a role for heteromerization in GPCR signalling specificity. Biochem. J., 2011, 433 (1), 11-8.
102. May, L. T.; Leach, K.; Sexton, P. M.; Christopoulos, A., Allosteric modulation of G protein-coupled receptors. Annu. Rev. Pharmacol. Toxicol., 2007, 47, 1-51.
103. Roche, D.; Gil, D.; Giraldo, J., Multiple active receptor conformation, agonist efficacy and maximum effect of the system: the conformation-based operational model of agonism. Drug Discov. Today, 2013, 18 (7-8), 365-71.
104. Hess, J. F. C. M. K.; McDonald, T. P.; Liverton, N.; McCauley, J. A.; Butcher, J. W.; Nguyen, K.; Charvin, D.; Campo, B.; Le Poul, E.; Reynolds, I. J., Novel mGluR4 Radioligands Reveal Distinct Sites for Positive Allosteric Modulators. Neuroscience, 2010, 2010, 40th Annual Meeting Society for Neuroscience (San Diego, CA, USA).
105. Drolet, R. T. K.; Liverton, N.; Vogel, R.; Reynolds, I. J.; Hess, F. J.; Renger, J. J.; Kern, J. T.; Celanire, S.; Tang, L.; Poli, S.; Campo, B.; Bortoli, J.; D'Addona, D., Binding property characterization of a novel mGluR4 positive allosteric modulator 2011.
106. Wang, J.-Q. K. D.; Brownell, A.-L., Radiosynthesis of (±)-N-(p-[11C]tolyl)-7-(hydroxyimino)cyclopropa[b]chromen-1acarboxamide ([11C]methyl-PHCCC) as a specific mGluR4 PET ligand. J. Nucl. Med., 2008, 49 (suppl 1), 288P.
107. Kil, K. E.; Zhang, Z.; Jokivarsi, K.; Gong, C.; Choi, J. K.; Kura, S.; Brownell, A. L., Radiosynthesis of N-(4-chloro-3-[(11)C]methoxyphenyl)-2-picolinamide ([(11)C]ML128) as a PET radiotracer for metabotropic glutamate receptor subtype 4 (mGlu4). Bioorg. Med. Chem., 2013, 21 (19), 5955-62.
108. 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), 4115-8.