Positive allosteric modulators for mglur2 receptors: A medicinal chemistry perspective

Current Topics in Medicinal Chemistry

Volumn 14, Issue 15, 2014, Pages 1771-1788

  Szabó, György ^a   Keserű, György Miklós ^b  

^a GEDEON RICHTER LTD   (Hungary)

^b INSTITUTE OF EXPERIMENTAL MEDICINE   (Hungary)

Author keywords

[No Author keywords available]

Indexed keywords

BENZIMIDAZOLE DERIVATIVE; BENZOTRIAZOLE DERIVATIVE; IMIDAZOLECARBOXAMIDE; IMIDAZOPYRIDINE DERIVATIVE; INDANONE DERIVATIVE; INDOLE; LY 487379; METABOTROPIC RECEPTOR 2; METABOTROPIC RECEPTOR 2 POSITIVE ALLOSTERIC MODULATOR; METABOTROPIC RECEPTOR AGONIST; METABOTROPIC RECEPTOR ANTAGONIST; METHAMPHETAMINE; OXAZOLIDINONE DERIVATIVE; PYRAZOLONE DERIVATIVE; SEROTONIN 2A RECEPTOR; SULFONAMIDE; UNCLASSIFIED DRUG; LIGAND; METABOTROPIC RECEPTOR; NEW DRUG; PSYCHOTROPIC AGENT;

ARTICLE; BINDING AFFINITY; CHEMICAL MODIFICATION; DRUG ACTIVITY; EC50; EXPERIMENTAL HYPERACTIVITY; GTPGAMMAS BINDING ASSAY; HIGH THROUGHPUT SCREENING; HUMAN; INTRACELLULAR SIGNALING; LIGAND BINDING; LIGAND EFFICIENCY DEPENDENT LIPOPHILICITY; LIGAND LIPOPHILICITY EFFICIENCY; LIPOPHILICITY; MEDICINAL CHEMISTRY; NONHUMAN; REACTION OPTIMIZATION; STRUCTURE ACTIVITY RELATION; SUBSTITUTION REACTION; AGONISTS; ALLOSTERISM; ANTAGONISTS AND INHIBITORS; ANXIETY; BINDING SITE; CHEMISTRY; CHILD DEVELOPMENT DISORDERS, PERVASIVE; DEPRESSION; DRUG DEVELOPMENT; FRAGILE X SYNDROME; METABOLISM; SCHIZOPHRENIA; SYNTHESIS;

ALLOSTERIC REGULATION; ALLOSTERIC SITE; ANXIETY; CHEMISTRY, PHARMACEUTICAL; CHILD DEVELOPMENT DISORDERS, PERVASIVE; DEPRESSION; DRUG DISCOVERY; DRUGS, INVESTIGATIONAL; FRAGILE X SYNDROME; HUMANS; LIGANDS; PSYCHOTROPIC DRUGS; RECEPTORS, METABOTROPIC GLUTAMATE; SCHIZOPHRENIA; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84925969086     PISSN: 15680266     EISSN: 18734294     Source Type: Journal    
DOI: 10.2174/1568026614666140826120716     Document Type: Article

References (143)

1. Kew, J.N.; Kemp, J.A. Ionotropic and metabotropic glutamate receptor structure and pharmacology. Psychopharmacology (Berl.), 2005, 179, 4-29.
2. Niswender, C.M.; Conn, P.J. Metabotropic glutamate receptors: physiology, pharmacology, and disease. Annu. Rev. Pharmacol. Toxicol., 2010, 50, 295–322.
3. Steckler, T.; Lavreysen, H.; Oliveira, A.M.; Aerts, N.; Van Craenendonck, H.; Prickaerts, J.; Megens, A.; Lesage, A.S. Effects of mGlu1 receptor blockade on anxietyrelated behaviour in the rat lick suppression test. Psychopharmacology (Berl), 2005, 179, 198– 206.
4. Varney, M.A.; Gereau, R.W. Metabotropic glutamate receptor involvement in models of acute and persistent pain: prospects for the development of novel analgesics. Curr. Drug Targets CNS Neurol. Disord., 2002, 1, 283–296.
5. Spooren, W.; Ballard, T.; Gasparini, F.; Amalric, M.; Mutel, V.; Schreiber, R. Insight into the function of Group I and Group II metabotropic glutamate (mGlu) receptors: behavioural characteriza tion and implications for the treatment of CNS disorders. Behav. Pharmacol., 2003, 14, 257–277.
6. Slassi, A.; Isaac, M.; Edwards, L.; Minidis, A.; Wensbo, D.; Mattsson, J.; Nilsson, K.; Raboisson, P.; McLeod, D.; Stormann, T.M.; Hammerland, L.G.; Johnson, E. Recent advances in noncompetitive mGlu5 receptor antagonists and their potential therapeutic applications. Curr. Top. Med. Chem., 2005, 5, 897-911.
7. Matosin, N.; Newell, K.A. Metabotropic Glutamate Receptor 5 in the Pathology and Treatment of Schizophrenia. Neurosci. Biobehav. Rev., 2013, 37, 256-268.
8. Lorrain, D.S.; Baccei, C.S.; Bristow, L.J.; Anderson, J.J.; Varney, M.A. Effects of ketamine and N-methyl-D-aspartate on glutamate and dopamine release in the rat prefrontal cortex: modulation by a group II selective metabotropic glutamate receptor agonist LY379268. Neuroscience, 2003, 117, 697–706.
9. Marek, G.J. Metabotropic glutamate 2/3 receptors as drug targets. Curr. Opin. Pharmacol., 2004, 4, 18–22.
10. Moghaddam, B.; Adams, B.W. Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats. Science, 1998, 281, 1349–1352.
11. Schoepp, D.D.; Marek, G.J. Preclinical pharmacology of mGlu2/3 receptor agonists: novel agents for schizophrenia? Curr. Drug Targets CNS Neurol. Disord., 2002, 1, 215–225.
12. Rorick-Kehn, L.M.; Johnson, B.G.; Knitowski, K.M.; Salhoff, C.R.; Witkin, J.M.; Perry, K.W.; Griffey, K.I.; Tizzano, J.P.; Monn, J.A.; McKinzie, D.L.; Schoepp, D.D. In vivo pharmacological characterization of the structurally novel, potent, selective mGlu2/3 receptor agonist LY404039 in animal models of psychiatric disorders. Psychopharmacology (Berl), 2007, 193, 121-36.
13. Witkin, J.M.; Marek, G.J.; Johnson, B.G.; Schoepp, D.D. Metabotropic Glutamate Receptors in the Control of Mood Disorders. CNS Neurol. Disord. -Drug. Targets, 2007, 6, 87-100.
14. Patil, S.T.; Zhang, L.; Martenyi, F.; Lowe, S.L.; Jackson, K.A.; Andreev, B.V.; Avedisova, A.S.; Bardenstein, L.M.; Gurovich, I.Y.; Morozova, M.A.; Mosolov, S.N.; Neznanov, N.G.; Reznik, A.M.; Smulevich, A.B.; Tochilov, V.A.; Johnson, B.G., Monn, J.A., Schoepp, D.D. Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial. Nat. Med., 2007, 13, 1102-7.
15. Mezler, M.; Geneste, H.; Gault, L.; Marek, G.J. LY-2140023, a prodrug of the group II metabotropic glutamate receptor agonist LY-404039 for the potential treatment of schizophrenia. Curr. Opin. Investig. Drugs, 2010, 11, 833e845.
16. Kinon, B. J.; Zhang, L.; Millen, B.A.; Osuntokun, O.O.; Williams, J.E.; Kollack-Walker, S.; Jackson, K.A.; Kryzhanovskaya, L.; Jarkova, N. A multicenter, inpatient, phase 2, double-blind, placebo-controlled dose-ranging study of LY2140023 monohydrate in patients with DSM-IV schizophrenia. J. Clin. Psychiatry, 2011, 31, 349-355.
17. Spooren, W.P.; Gasparini, F.; Bergmann, R.; Kuhn, R. Effects of the prototypical mGlu(5) receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine on rotarod, locomotor activity and rotational responses in unilateral 6-OHDA-lesioned rats. Eur. J. Pharmacol, 2000, 406, 403-10.
18. Fell, M.J.; Svensson, K.A.; Johnson, B.G.; Schoepp, D.D. Evidence for the role of metabotropic glutamate (mGlu)2 not mGlu3 receptors in the preclinical antipsychotic pharmacology of the mGlu2/3 receptor agonist (-)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo [3.1.0]hexane-4,6-dicarboxylic acid (LY404039). J. Pharmacol. Exp. Ther., 2008, 326, 209-17.
19. Rowe, B.A.; Schaffhauser, H.; Morales, S.; Lubbers, L.S.; Bonnefous, C.; Kamenecka, T.M.; McQuiston, J.; Daggett, L.P. 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,. 2008, 326, 240-251.
20. Conn, P.J.; Lindsley, C.W.; Jones, C.K. Activation of metabotropic glutamate receptors as a novel approach for the treatment of schizophrenia Trends Pharmacol. Sci., 2009, 30, 25–31.
21. Rudd, M.T.; McCauley, J.A. Positive allosteric modulators of the metabotropic glutamate receptor subtype 2 (mGluR2). Curr. Top. Med. Chem., 2005, 5, 869-84.
22. Johnson, M.P.; Baez, M.; Jagdmann, G.E. Jr.; Britton, T.C.; Large, T.H.; Callagaro, D.O.; Tizzano, J.P.; Monn, J.A.; Schoepp, D.D. Discovery of allosteric potentiators for the metabotropic glutamate 2 receptor: synthesis and subtype selectivity of N-(4-(2-methoxyphenoxy)phenyl)-N-(2,2,2-trifluoroethylsulfonyl)pyrid-3-ylmethylamine. J. Med. Chem., 2003, 46, 3189–3192.
23. Johnson, M.P.; Barda, D.; Britton, T.C.; Emkey, R.; Hornback, W.J.; Jagdmann, G.E.; McKinzie, D.L.; Nisenbaum, E.S.; Tizzano, J.P.; Schoepp, D.D. Metabotropic glutamate 2 receptor potentiators: receptor modulation, frequency-dependent synaptic activity and efficacy in preclinical anxiety and psychosis model(s). Psychopharmacology, 2005, 179, 271–283.
24. Galici, R.; Echemendia, N.G.; Rodriguez, A.L.; Conn, P.J. A selective allosteric potentiator of metabotropic glutamate (mGlu) 2 receptors has effects similar to an orthosteric mGlu2/3 receptor agonist in mouse models predictive of antipsychotic activity. J. Pharmacol. Exp. Ther, 2005, 315, 1181–1187.
25. Hopkins, C.R. Is There a Path Forward for mGlu2 Positive Allosteric Modulators for the Treatment of Schizophrenia? ACS Chem. Neurosci., 2013, 4, 211-213.
26. Fraley, M.E. Positive allosteric modulators of the metabotropic glutamate receptor 2 for the treatment of schizophrenia. Expert Opin. Ther. Pat., 2009, 19, 1259-75.
27. Eli Lilly and Company. Potentiators of glutamate receptors. WO2001056990, 2001
28. Johnson, M.P.; Baez, M.; Jagdmann, G.E.; Britton, T.C.; Large, T.H.; Callagaro, D.O.; Tizzano, J.P.; Monn, J.A.; Schoepp, D.D. Discovery of allosteric potentiators for the metabotropic glutamate 2 receptor: synthesis and subtype selectivity of N-(4-(2-methoxyphenoxy)phenyl)-N-(2,2,2-trifluoroethylsulfonyl)pyrid-3-ylmethylamine. J. Med. Chem., 2003, 46, 3189-92.
29. Johnson, M.P.; Barda, D.; Britton, T.C. Britton, T.C.; Large, T.H.; Callagaro, D.O.; Tizzano, J.P.; Monn, J.A.; Schoepp, D.D. Metabotropic glutamate receptor 2 potentiators: receptor modulation, frequency-dependent synaptic activity, and efficacy in preclinical anxiety and psychosis model(s). Psychopharmacology (Berl), 2005, 179, 271-83.
30. Merck & Co., Inc. Pyrimidine and quinoline potentiators of metabotropic glutamate receptors. WO2006049968; 2006
31. Hu, E.; Chua, P.C.; Tehrani, L.; Nagasawa, J.Y.; Pinkerton, A.B.; Rowe, B.A.; Vernier, J.M.; Hutchinson, J.H.; Cosford, N.D. Pyrimidine methyl anilines: selective potentiators for the metabotropic glutamate 2 receptor. Bioorg. Med. Chem. Lett. 2004, 14, 5071-4.
32. Merck & Co., Inc. Indanone potentiators of metabotropic glutamate receptors. WO2006015158; 200
33. Bonnefous, C.; Vernier, J.-M.; Hutchinson, J.H.; Gardner, M.F.; Cramer, M.; James, J.K.; Rowe, B.A.; Daggett, L.P.; Schaffhauser, H.; Kamenecka, T.M. Biphenyl-indanones: allosteric potentiators of the metabotropic glutamate subtype 2 receptor. Bioorg. Med. Chem. Lett., 2005, 15, 4354-8.
34. Galici, R.; Echemendia, N.G.; Rodriquez, A.L.; Conn, P.J. A selective allosteric potentiator of metabotropic glutamate (mGlu) 2 receptors has effects similar to an orthosteric mGluR2/3 receptor agonist in mouse models predictive of antipsychotic activity. J. Pharmacol. Exp. Ther., 2005, 315, 1181-7.
35. Galici, R.; Jones, C.K.; Hemstapat, K.; Nong, Y.; Echemendia, N.G.; Williams, L.C.; de Paulis, T.; Conn, P.J. 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., 2006, 318, 173-85
36. Pinkerton, A.B.; Cube, R.V.; Hutchinson, J.H.; James, J.K.; Gardner, M.F.; Rowe, B.A.; Schaffhauser, H.; Rodriguez, D.E.; Campbell, U.C.; Daggett, L.P.; Vernier, J.M. Allosteric potentiators of the metabotropic glutamate receptor 2 (mGluR2). Part 3: identification and biological activity of indanone containing mGlu2 receptor potentiators. Bioorg. Med. Chem. Lett., 2005, 15, 1565-71.
37. Merck & Co., Inc. Acetophenone potentiators of metabotropic glutamate receptors. WO2004018386; 2004
38. Merck & Co., Inc. Heterocyclic acetophenone potentiators of metabotropic glutamate receptors. WO2006014918; 2006
39. Pinkerton, A.B.; Vernier, J.-M.; Schaffhauser, H.; Rowe, B.A.; Schaffhauser, H.; Zhao, X.; Daggett, L.P.; Vernier, J.M. Phenyltetrazoyl acetophenones: discovery of positive allosteric potentiators for the metabotropic glutamate 2 receptor. J. Med. Chem., 2004, 47, 4595-9.
40. Pinkerton, A.B.; Cube, R.V.; Hutchinson, J.H.; Rowe, B.A.; Schaffhauser, H.; Zhao, X.; Daggett, L.P.; Vernier, J.M. Allosteric potentiators of the metabotropic glutamate receptor 2 (mGluR2). Part 1: identification and synthesis of phenyl-tetrazolyl acetophenones. Bioorg. Med. Chem. Lett., 2004, 14, 5329-32.
41. Pinkerton, A.B.; Cube, R.V.; Hutchinson, J.H.; James, J.K.; Gardner, M.F.; Schaffhauser, H., Rowe, B.A.; Daggett, L.P.; Vernier, J.M. Allosteric potentiators of the metabotropic glutamate receptor 2 (mGluR2). Part 2: 4-thiopyridyl acetophenones as nontetrazole containing mGlu2 receptor potentiators. Bioorg. Med. Chem. Lett., 2004, 14, 5867-72.
42. Cube, R.V.; Vernier, J.-M.; Hutchinson, J.H.; Gardner, M.F.; James, J.K.; Rowe, B.A.; Schaffhauser, H.; Daggett, L.; Pinkerton, A.B. 3-(2-Ethoxy-4-{4-[3-hydroxy-2-methyl-4-(3-methylbuta-noyl)-phenoxy]butoxy}phenyl)propanoic acid: a brain penetrant allosteric potentiator at the metabotropic glutamate receptor 2 (mGluR2). Bioorg. Med. Chem. Lett., 2005, 15, 2389-93
43. Eli Lilly and Company. Potentiators of glutamate receptors. WO2006057869; 2006
44. Eli Lilly and Company. Potentiators of glutamate receptors. WO2006057870; 2006
45. A study in migraine prevention (NCT01184508) ClinicalTrials.gov Web Site 2010, September 06.
46. Eli Lilly and Co. Imidazole carboxamides. WO2010009062; 2010
47. Fell, M.J.; Witkin, J.M.; Falcone, J.F.; Katner, J.S.; Perry, K.W; Hart, J.; Rorick-Kehn, L.; Overshiner, C.D.; Rasmussen, K.; Chaney, S.F.; Benvenga, M.J.; Li, X.; Marlow, D.L.; Thompson, L.K.; Luecke, S.K.; Wafford, K.A.; Seidel, W.F.; Edgar, D.M.; Quets, A.T.; Felder, C.C.; Wang, X.; Heinz, B.A.; Nikolayev, A.; Kuo, M.S.; Mayhugh, D.; Khilevich, A.; Zhang, D.; Ebert, P.J.; Eckstein, J.A.; Ackermann, B.L.; Swanson, S.P.; Catlow, J.T.; Dean, R.A.; Jackson, K.; Tauscher-Wisniewski, S.; Marek, G.J.; Schkeryantz, J.M.; Svensson, K.A. 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 change. J. Pharmacol. Exp. Ther., 2011, 336, 165-77.
48. Janssen Pharmaceutica N.V. and Addex Pharmaceuticals S.A. Novel pyridinone derivatives and their use as positive allosteric modulators of mGluR2-receptors. WO2006030032; 2006
49. Maria, J.S.; Duvey, G.; Cluzeau, P.; Nhem, V.; Macary, K.; Raux, A.; Poirier, N.; Muller, J.; Boléa, C.; Finn, T.; Poli, S.; Epping-Jordan, M.; Chamelot, E.; Derouet, F.; Girard, F.; Macdonald, G.J.; Vega, J.A.; de Lucas, AI.; Matesanz, E.; Lavreysen, H.; Linares, M.L.; Oehlrich, D.; Oyarzábal, J.; Tresadern, G.; Trabanco, A.A.; Andrés, J.I.; Le Poul, E.; Imogai, H.; Lutjens, R.; Rocher, J.P. Discovery of 1,5-Disubstituted Pyridones: A New Class of Positive Allosteric Modulators of the Metabotropic Glutamate 2 Receptor. ACS Chem. Neurosci., 2010, 1, 788-95
50. Janssen Pharmaceutica N.V. and Addex Pharmaceuticals S.A. 1,4-Disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of mGluR2-receptors. WO2007104783; 2007
51. Janssen Pharmaceutica N.V. and Addex Pharmaceuticals S.A. 3-Cyano-4-(4-phenyl-piperidin-1yl)-pyridin-2-one derivatives. WO2-008107479; 2008
52. Janssen Pharmaceutica N.V. and Addex Pharmaceuticals S.A. 1,4-Disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of mGluR2-receptors. WO2008107480; 2008
53. Janssen Pharmaceutica N.V. and Addex Pharmaceuticals S.A. 3-Cyano-4-(4-tetrahydropyran-phenyl)-pyridin-2-one pyridone derivatives. WO2008107481; 2008
54. Lavreysen, H.; Langlois, X.; Ahnaou, A.; Drinkenburg, W.; te Riele, P.; Biesmans, I.; Van der Linden, I.; Peeters, L.; Megens, A.; Wintmolders, C.; Cid, J.M.; Trabanco, A.A.; Andrés, J.I.; Dautzenberg, F.M.; Lütjens, R.; Macdonald, G.; Atack, J.R. 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., 2013, 346, 514-527
55. Ortho-McNeil-Janssen Pharmaceuticals, Inc. and Addex Pharmaceuticals S.A. 1´,3´-Disubstituted-4-phenyl-3,4,5,6-tetrahydro-2H,1´H-[1,4´]bipyridinyl-2´-ones. WO2009033704; 2009
56. Ortho-McNeil-Janssen Pharmaceuticals, Inc. and Addex Pharmaceuticals S.A. 1,3-Disubstituted 4-(aryl-x-phenyl)-1H-pyridin-2-ones. WO2009033702; 2009
57. Ortho-McNeil-Janssen Pharmaceuticals, Inc. and Addex Pharmaceuticals S.A. 1,3-Disubstituted-4-phenyl-1H-pyridin-2-ones. WO-2009033703; 2009
58. Ortho-McNeil-Janssen Pharma, Inc. And Addex Pharmaceuticals S.A. 3-Azabicyclo[3.1.0]hexyl derivatives as modulators of metabotropic glutamate receptors. WO2010025890; 2010
59. Ortho-McNeil-Janssen Pharmaceuticals, Inc. and Addex Pharma S.A. Indole and benzomorpholine derivatives as modulators of metabotropic glutamate receptors. WO2010043396; 2010
60. AstraZeneca AB and NPS Pharmaceuticals, Inc. Isoindolone compounds and their use as metabotropic glutamate receptor potentiators. WO2006020879; 2006
61. AstraZeneca AB and NPS Pharmaceuticals, Inc. Metabotropic glutamate-receptor-potentiating isoindolones. WO2007021308; 2007
62. AstraZeneca AB and NPS Pharmaceuticals, Inc. Substituted isoindolones and their use as metabotropic glutamate receptor potentiators. WO2007021309; 2007
63. AstraZeneca AB. Metabotropic glutamate receptor oxadiazole ligands and their use as potentiators. WO2008150232; 2008
64. AstraZeneca AB. Oxadiazole derivatives and their use as metabotropic glutamate receptor potentiators. WO2008150233; 2008
65. AstraZeneca AB. Polymorphs of metabotropic glutamate receptor positive allosteric modulator. WO2011136723; 2011
66. AstraZeneca AB and NPS Pharmaceuticals, Inc. Metabotropic glutamate-receptor-potentiating isoindolones. WO2007095024; 2007
67. AstraZeneca AB. Aza-isoindolones and their use as metabotropic glutamate receptor potentiators. WO2008100715; 2008
68. AstraZeneca AB. Hydrazides and their use as metabotropic glutamate receptor potentiators. WO2008130853; 2008
69. AstraZeneca AB. Isoxazole derivatives and their use as metabotropic glutamate receptor potentiators. WO2009148403; 2009
70. Abbott GMBH & Co. KG. Heterocyclic compounds as positive modulators of metabotropic glutamate receptor 2 (mGlu2 receptor). WO2008145616; 2008
71. González-Maeso, J.; Ang, R.L.; Yuen, T.; Chan, P.; Weisstaub, N.V.; López-Giménez, J.F.; Zhou, M.; Okawa, Y.; Callado, L.F.; Milligan, G.; Gingrich, J.A.; Filizola, M.; Meana, J.J.; Sealfon, S.C. (2008) Identification of a Serotonin/Glutamate Receptor Complex implicated in psychosis. Nature, 2008, 452, 93-99.
72. Molinaro, G.; Traficante, A.; Riozzi, B.; Di Menna, L.; Curto, M.; Pallottino, S.; Nicoletti, F.; Bruno, V.; Battaglia, G. Activation of mGlu2/3 Metabotropic Glutamate Receptors Negatively Regulates the Stimulation of Inositol Phospholipid Hydrolysis Mediated by 5-Hydroxytryptamine 2A Serotonin Receptors in the Frontal Cortex of Living Mice. Mol. Pharmacol., 2009, 76, 379–387.
73. González-Maeso, J.; Weisstaub, N.V.; Zhou, M.; Chan, P.; Ivic, L.; Ang, R.; Lira, A.; Bradley-Moore, M.; Ge, Y.; Zhou, Q.; Sealfon, S.C.; Gingrich, J.A. Hallucinogens Recruit Specific Cortical 5-HT2A Receptor-Mediated Signaling Pathways to Affect Behavior. Neuron., 2007, 53, 439-452
74. Schmid, C.L.; Raehal, K.M.; Bohn, L.M. Agonist-directed Signaling of the Serotonin 2A Receptor Depends on _-arrestin-2 Interactions in vivo. Proc. Natl. Acad. Sci. USA, 2008, 105, 1079–1084.
75. Liu, W.; Downing, A.C.; Munsie, L.M.; Chen, P.; Reed, M.R.; Ruble, C.L.; Landschulz, K.T.; Kinon, B.J.; Nisenbaum, L.K. Pharmacogenetic analysis of the mGlu2/3 agonist LY2140023 monohydrate in the treatment of schizophrenia. Pharmacogenomics J., 2012, 12, 246-54.
76. Abbott GmbH & Co. KG. Novel small molecule potentiators of metabotropic glutamate receptors. US2011245247; 2011
77. Abbott GmbH & Co. KG. Novel small molecule potentiators of metabotropic glutamate receptors I. US2011245232; 2011
78. N.V. Organon. Heterocyclic derivatives. WO2011051490; 2011
79. Sanford-Burnham Medical Research Institute. Positive allosteric modulators of group II mGluRs. WO2011116356; 2011
80. Sidique, S.; Dhanya, R.-P.; Sheffler, D.J.; Nickols, H.H.; Yang, L.; Dahl, R.; Mangravita-Novo, A.; Smith, L.H.; D'Souza, M.S.; Semenova, S.; Conn, P.J.; Markou, A.; Cosford, N.D. Orally active metabotropic glutamate subtype 2 receptor positive allosteric modulators: structure-activity relationships and assessment in a rat model of nicotine dependence. J. Med. Chem., 2012, 55, 9434-45.
81. AstraZeneca AB and NPS Pharmaceuticals, Inc. Oxazolidinone compounds and their use as metabotropic glutamate receptor potentiators. WO2007078523; 2007
82. AstraZeneca AB. Spiro-oxazolidinone compounds and their use as metabotropic glutamate receptor potentiators. WO2008032191; 2008
83. Pfizer, Inc. N-Benzyl oxazolidinones and related heterocyclic compounds as potentiators of glutamate receptors. WO2009004430; 2009
84. Duplantier, A.J.; Efremov, I.; Candler, J.; Doran, A.C.; Ganong, A.H.; Haas, J.A.; Hanks, A.N.; Kraus, K.G.; Lazzaro, J.T. Jr.; Lu, J.; Maklad, N.; McCarthy, S.A.; O'Sullivan, T.J.; Rogers, B.N.; Siuciak, J.A.; Spracklin, D.K.; Zhang, L. 3-Benzyl-1,3-oxazolidin-2-ones as mGluR2 positive allosteric modulators: hit-to-lead and lead optimization. Bioorg. Med. Chem. Lett., 2009, 19, 2524-9.
85. Merck & Co., Inc. 3,5-Substitured-1,3-oxazolidin-2-one derivatives. WO2009094265;2009
86. Brnardic, E.J.; Fraley, M.E.; Garbaccio, R.M.; Layton, M.E.; Sanders, J.M.; Culberson, C.; Jacobson, M.A.; Magliaro, B.C.; Hutson, P.H.; O'Brien, J.A.; Huszar, S.L.; Uslaner, J.M.; Fillgrove, K.L.; Tang, C.; Kuo, Y.; Sur, S.M.; Hartman, G.D. 3-Aryl-5-phenoxymethyl-1,3-oxazolidin-2-ones as positive allosteric modulators of mGluR2 for the treatment of schizophrenia: hit-to-lead efforts. Bioorg. Med. Chem. Lett., 2010, 20, 3129-33.
87. Merck & Co., Inc. Oxazolobenzimidazolone derivatives. WO2009140163; 2009
88. Merck & Co., Inc.Oxazolobenzimidazolone derivatives. WO2009140166; 2009
89. Merck & Co., Inc. Oxazolobenzimidazolone derivatives. WO2010036544; 2010
90. Garbaccio, R.M.; Brnardic, E.J.; Fraley, M.E.; Hartman, G.D.; Hutson, P.H.; O'Brien, J.A.; Magliaro, B.C.; Uslaner, J.M.; Huszar, S.L.; Fillgrove, K.L.; Small, J.H.; Tang, C.; Kuo, Y.; Jacobson, M.A. Discovery of oxazolobenzimidazoles as positive allosteric modulators for the mGluR2 receptor. ACS Med. Chem. Lett., 2010, 1, 406-10.
91. Taisho Pharmaceutical Co., Ltd. Dihydroimidazooxazole derivatives. WO2013062079; 2013
92. Sanofi-Aventis. Substituted dihydro and tetrahydro oxazolopyrimidinones, preparation and use thereof. WO2008112483; 2008
93. Sanofi-Aventis. Substituted dihydro, trihydro and tetrahydro cycloalkyloxazolopyrimidones, preparation and use thereof as allosteric modulators of mGluR. WO2009110901;2009
94. Sanofi-Aventis. Substituted para-biphenyloxymethyl dihydro oxazolopyrimidones, preparation and use thereof. WO2011034828; 2011
95. Sanofi-Aventis. Substituted benzocycloalkyloxymethyl oxazolopyrimidones, preparation and use thereof. WO2011034830; 2011
96. Sanofi-Aventis. Substituted phenoxymethyl dihydro oxazolopyrimidones, preparation and use thereof. WO2011034832; 2011
97. Merck & Co., Inc. Benzazole potentiators of metabotropic glutamate receptors. WO2006091496; 2006
98. Govek, S.P.; Bonnefous, C.; Hutchinson, J.H.; Kamenecka, T.; McQuiston, J.; Pracitto, R.; Zhao, L.X.; Gardner, M.F.; James, J.K.; Daggett, L.P.; Rowe, B.A.; Schaffhauser, H.; Bristow, L.J.; Campbell, U.C.; Rodriguez, D.E.; Vernier, J.M. Benzazoles as allosteric potentiators of metabotropic glutamate receptor 2 (mGluR2): efficacy in an animal model of schizophrenia. Bioorg. Med. Chem. Lett., 2005, 15, 4068-72.
99. AstraZeneca AB and NPS Pharmaceuticals, Inc. Bicyclic benzimidazole compounds and their use as metabotropic glutamate receptor potentiators. WO2007115077; 2007
100. Pfizer Products, Inc. Benzimidazolyl compounds as potentiators of mGluR2 subtype of glutamate receptor. WO2008012623; 2008
101. Pfizer Products, Inc. Benzimidazolyl compounds. WO2007135527; 2007.
102. Pfizer Products, Inc. Azabenzimidazolyl compounds. WO2008012622; 2008
103. Pfizer Products, Inc. Benzimidazolyl compounds. WO2007135529; 2007
104. Zhang, L.; Rogers, B.N.; Duplantier, A.J.; McHardy, S.F.; Efremov, I.; Berke, H.; Qian, W.; Zhang, A.Q.; Maklad, N.; Candler, J.; Doran, A.C.; Lazzaro, J.T. Jr.; Ganong, A.H. 3-(Imidazoyl methyl)-3-aza-bicyclo[3.1.0]hexan-6-ylmethyl ethers: A novel series of mGluR2 positive allosteric modulators. Bioorg. Med. Chem. Lett., 2008, 18, 5493-6.
105. Merck Sharp & Dohme Corp. Aminobenzotriazole derivatives. WO2010114726; 2010.
106. Merck Sharp & Dohme Corp. Aminobenzotriazole derivatives. WO2010141360; 2010.
107. Merck Sharp & Dohme Corp. Ether benzotriazole derivatives. WO2011022312; 2011.
108. Merck Sharp & Dohme Corp. Ether benzotriazole derivatives. US2012135977; 2012.
109. Merck Sharp & Dohme Corp. Aminomethyl biaryl benzotriazole derivatives. WO2012151136; 2012.
110. Merck Sharp & Dohme Corp. Hydroxymethyl biaryl benzotriazole derivatives. WO2012151140; 2012.
111. Merck Sharp & Dohme Corp. Cyclohenexe benzotriazole derivatives. WO2012151138; 2012.
112. Merck Sharp & Dohme Corp. Alkyne benzotriazole derivatives. WO2012151139; 2012.
113. Merck Sharp & Dohme Corp. Imidazopyridin-2-one derivatives. WO2011034741; 2011.
114. Merck Sharp & Dohme Corp. Positive allosteric modulators of mGluR2. WO2011156245; 2011.
115. Merck Sharp & Dohme Corp. Imidazopyridin-2-one derivatives. WO2012174199; 2012.
116. Merck Sharp & Dohme Corp. Positive allosteric modulators of mGluR2. WO2012021382; 2012.
117. Merck Sharp & Dohme Corp. Positive allosteric modulators of mGluR2. WO2011109277; 2011.
118. Merck Sharp & Dohme Corp. Substituted 1,3-benzothiazol-2(3H)-ones and [1,3]thiazolo[5,4-b]pyridine-2(1H)-ones as positive allosteric modulators in mGluR2. WO2011137046; 2011.
119. Tresadern, G.; Cid, J.; Macdonald, G.J.; Vega, J.A.; de Lucas, AI.; García, A.; Matesanz, E.; Linares, M.L.; Oehlrich, D.; Lavreysen, H.; Biesmans, I.; Trabanco, A.A. Scaffold hopping from pyridones to imidazo[1,2-a]pyridines. New positive allosteric modulators of metabotropic glutamate 2 receptor. Bioorg. Med. Chem. Lett., 2010, 20, 175-9.
120. Ortho-McNeil-Janssen Pharmaceuticals, Inc. and Addex Pharma S.A. Imidazo[1,2-a]pyridine derivatives as positive allosteric modulators of mGluR2 receptors. WO2009062676; 2009.
121. Ortho-McNeil-Janssen Pharmaceuticals, Inc. and Addex Pharma S.A. Indole and benzoxazine derivatives as modulators of metabotropic glutamate receptors. WO2010060589; 2010.
122. Trabanco, A.A.; Tresadern, G.; Macdonald, G.J.; Vega, J.A.; de Lucas, AI.; Matesanz, E.; García, A.; Linares, M.L.; Alonso de Diego, S.A.; Alonso, J.M.; Oehlrich, D.; Ahnaou, A.; Drinkenburg, W.; Mackie, C.; Andrés, J.I.; Lavreysen, H.; Cid, J.M. Imidazo[1,2-a]pyridines: orally active positive allosteric modulators of the metabotropic glutamate receptor 2. J. Med. Chem., 2012, 55, 2688-701.
123. Ortho-McNeil-Janssen Pharmaceuticals, Inc. and Addex Pharma S.A. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors. WO2010130422; 2010.
124. Ortho-McNeil-Janssen Pharmaceuticals, Inc. and Addex Pharma S.A. 7-aryl-1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors. WO2010130423; 2010.
125. Ortho-McNeil-Janssen Pharmaceuticals, Inc. and Addex Pharma S.A. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use for the treatment or prevention of neurological and psychiatric disorders. WO2010130424; 2010.
126. Cid, J.M.; Tresadern, G.; Vega, J.A.; de Lucas, A.I.; Matesanz, E.; Iturrino, L.; Linares, M.L.; Garcia, A.; Andrés, J.I.; Macdonald, G.J.; Oehlrich, D.; Lavreysen, H.; Megens, A.; Ahnaou, A.; Drinkenburg, W.; Mackie, C.; Pype, S.; Gallacher, D.; Trabanco, A.A. Discovery of 3-cyclopropylmethyl-7-(4-phenyl-piperidin-1-yl)-8-trifluoromethyl[1,2,4]triazolo[4,3a] pyridine (JNJ-42153605): a positive allosteric modulator of the metabotropic glutamate 2 receptor. J. Med. Chem., 2012, 55, 8770-89.
127. Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors. WO2012062750; 2012.
128. Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors. WO2010062751; 2012.
129. Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors. WO2010062759; 2012.
130. Janssen Pharmaceuticals, Inc. Radiolabelled mGluR2 PET ligands. WO2010062752; 2012.
131. Andres, J.-I.; Alcazar, J.; Cid, J.M.; De Angelis, M.; Iturrino, L.; Langlois, X.; Lavreysen, H.; Trabanco, A.A.; Celen, S.; Bormans, G. Synthesis, evaluation, and radiolabeling of new potent positive allosteric modulators of the metabotropic glutamate receptor 2 as potential tracers for positron emission tomography imaging. J. Med. Chem., 2012, 55, 8685-99.
132. AstraZeneca AB and NPS Pharmaceuticals, Inc. Substituted benzosulphonamide as potentiators of glutamate. WO2004092135; 2004.
133. AstraZeneca AB and NPS Pharmaceuticals, Inc. Pyrazolone compounds as metabotropic glutamate receptor agonists for the treatment of neurological and psychiatric disorders. WO2006071730; 2006.
134. Janssen Pharmaceutica N.V. and Addex Pharmaceuticals S.A. Novel thieno-pyridine and thieno-pyrimidine derivatives and their use as positive allosteric modulators of mGluR2-receptors. WO2006030031; 2006.
135. Taisho Pharmaceutical Co., Inc. Imidazolone derivative. WO2013062074; 2013.
136. Dainippon Sumitomo Pharma Co., Ltd. Dihydroimidazo pyrazinone derivative. JP2013166727; 2013.
137. Thomson Reuters Integrity database is available at https://integrity.thomson-pharma.com/integrity, 15 April, 2014.
138. Hopkins, A.L.; Groom, C.R.; Alex, A. Ligand efficiency: a useful metric for lead selection. Drug Discov., Today, 2004, 9, 430–431.
139. Leeson, P.D.; Springthorpe, B. The influence of drug-like concepts on decision-making in medicinal chemistry. Nature Rev. Drug Discov. 2007, 6, 881–890.
140. Keserű, G.M.; Makara, G.M. The influence of lead discovery strategies on the properties of drug candidates. Nature Rev. Drug Discov., 2009, 8, 203–212.
141. Hopkins, A.L.; Keserű, G.M.; Leeson, P.D.; Rees, D.C.; Reynolds, C.H. The role of ligand efficiency metrics in drug discovery. Nature Rev. Drug Discov., 2014, 13, 105-121.
142. Tarcsay, A.; Nyíri, K.; Keserű, G.M. Impact of lipophilic efficiency on compound quality. J. Med. Chem., 2012, 55, 1252-1260.
143. Wager, T.T.; Chandrasekaran, R.Y.; Hou, X.; Troutman, M.D.; Verhoest, P.R.; Villalobos, A.; Will, Y. Defining Desirable Central Nervous System Drug Space through the Alignment of Molecular Properties, in vitro ADME, and Safety Attributes. ACS Chem. Neurosci., 2010, 1, 420–434.