Activation of metabotropic glutamate receptors as a novel approach for the treatment of schizophrenia

Trends in Pharmacological Sciences

Volumn 30, Issue 1, 2009, Pages 25-31

  Conn, P Jeffrey ^a   Lindsley, Craig W ^a,b   Jones, Carrie K ^a  

^a VANDERBILT UNIVERSITY MEDICAL CENTER   (United States)

^b VANDERBILT UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1,2 BIS(3 FLUOROBENZYLIDENE)HYDRAZINE; 2,3,2 TRIFLUORO N [4 (2 METHOXYPHENOXY)PHENYL] N (PYRIDIN 3 YLMETHYL)ETHANESULFONAMIDE; 3 CYANO N (1,3 DIPHENYL 1H PYRAZOL 5 YL)BENZAMIDE; 4' [(2 CYCLOPENTYL 6,7 DIMETHYL 1 OXO 2,3 DIHYDRO 1H INDEN 5 YLOXY)METHYL]BIPHENYL 4 CARBOXYLIC ACID; ADX 47273; EGLUMETAD; LY 487379; METABOTROPIC RECEPTOR; METABOTROPIC RECEPTOR 2; METABOTROPIC RECEPTOR 3; METABOTROPIC RECEPTOR 5; METABOTROPIC RECEPTOR AGONIST; N [5 CHLORO 2 [(1,3 DIOXOISOINDOLIN 2 YL)METHYL]PHENYL] 2 HYDROXYBENZAMIDE; UNCLASSIFIED DRUG;

ALLOSTERISM; BINDING SITE; DRUG RECEPTOR BINDING; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG TARGETING; HUMAN; NONHUMAN; PRIORITY JOURNAL; PROTEIN DOMAIN; REVIEW; SCHIZOPHRENIA;

ALLOSTERIC REGULATION; ANIMALS; DRUG DELIVERY SYSTEMS; DRUG DISCOVERY; HUMANS; MODELS, THEORETICAL; RECEPTORS, METABOTROPIC GLUTAMATE; SCHIZOPHRENIA;

EID: 58149119377     PISSN: 01656147     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.tips.2008.10.006     Document Type: Review

References (65)

1. Meltzer H.Y. Treatment of schizophrenia and spectrum disorders: pharmacotherapy, psychosocial treatments, and neurotransmitter interactions. Biol. Psychiatry 46 (1999) 1321-1327
2. Tan H.Y., et al. Dysfunctional and compensatory prefrontal cortical systems, genes and the pathogenesis of schizophrenia. Cereb. Cortex 17 Suppl 1 (2007) i171-i181
3. Conn, P.J. et al. (2008b) Schizophrenia: moving beyond monoamine antagonists. Mol. Interv. 8, 99-107
4. Nikam S.S., and Awasthi A.K. Evolution of schizophrenia drugs: a focus on dopaminergic systems. Curr. Opin. Investig. Drugs 9 (2008) 37-46
5. Toda M., and Abi-Dargham A. Dopamine hypothesis of schizophrenia: making sense of it all. Curr. Psychiatry Rep. 9 (2007) 329-336
6. Carlsson A., et al. Neurotransmitter aberrations in schizophrenia: new perspectives and therapeutic implications. Life Sci. 61 (1997) 75-94
7. Lisman J.E., et al. Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia. Trends Neurosci. 31 (2008) 234-242
8. Carlsson A. The neurochemical circuitry of schizophrenia. Pharmacopsychiatry 39 Suppl. 1 (2006) S10-S14
9. Lewis D.A., and Moghaddam B. Cognitive dysfunction in schizophrenia: convergence of gamma-aminobutyric acid and glutamate alterations. Arch. Neurol. 63 (2006) 1372-1376
10. Coyle J.T. Glutamate and schizophrenia: beyond the dopamine hypothesis. Cell. Mol. Neurobiol. 26 (2006) 365-384
11. Lindsley C.W., et al. Progress towards validating the NMDA receptor hypofunction hypothesis of schizophrenia. Curr. Top. Med. Chem. 6 (2006) 771-785
12. Chavez-Noriega L.E., et al. Novel potential therapeutics for schizophrenia: focus on the modulation of metabotropic glutamate receptor function. Curr. Neuropharmacol. 3 (2005) 9-34
13. Marino M.J., and Conn P.J. Direct and indirect modulation of the N-methyl D-aspartate receptor. Curr. Drug Targets CNS Neurol. Disord. 1 (2002) 1-16
14. Liu J., and Moghaddam B. Regulation of glutamate efflux by excitatory amino acid receptors: evidence for tonic inhibitory and phasic excitatory regulation. J. Pharmacol. Exp. Ther. 274 (1995) 1209-1215
15. Lorrain D.S., et al. 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 117 (2003) 697-706
16. Moghaddam B., et al. Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J. Neurosci. 17 (1997) 2921-2927
17. Aghajanian G.K., and Marek G.J. Serotonin model of schizophrenia: emerging role of glutamate mechanisms. Brain Res. Brain Res. Rev 31 (2000) 302-312
18. Sharp F.R., et al. Psychosis: pathological activation of limbic thalamocortical circuits by psychomimetics and schizophrenia?. Trends Neurosci. 24 (2001) 330-334
19. Ugolini A., et al. Potentiation of NMDA and AMPA responses by the specific mGluR5 agonist CHPG in spinal cord motoneurons. Neuropharmacology 38 (1999) 1569-1576
20. Awad H., et al. Activation of metabotropic glutamate receptor 5 has direct excitatory effects and potentiates NMDA receptor currents in neurons of the subthalamic nucleus. J. Neurosci. 20 (2000) 7871-7879
21. Doherty A.J., et al. A novel, competitive mGlu(5) receptor antagonist (LY344545) blocks DHPG-induced potentiation of NMDA responses but not the induction of LTP in rat hippocampal slices. Br. J. Pharmacol. 131 (2000) 239-244
22. Attucci S., et al. Activation of type 5 metabotropic glutamate receptors enhances NMDA responses in mice cortical wedges. Br. J. Pharmacol. 132 (2001) 799-806
23. Mannaioni G., et al. Metabotropic glutamate receptors 1 and 5 differentially regulate CA1 pyramidal cell function. J. Neurosci. 21 (2001) 5925-5934
24. Pisani A., et al. Metabotropic glutamate receptor 5 mediates the potentiation of N-methyl-D-aspartate responses in medium spiny striatal neurons. Neuroscience 106 (2001) 579-587
25. Jia Z., et al. Selective abolition of the NMDA component of long-term potentiation in mice lacking mGluR5. Learn. Mem. 5 (1998) 331-343
26. Lu Y.M., et al. Mice lacking metabotropic glutamate receptor 5 show impaired learning and reduced CA1 long-term potentiation (LTP) but normal CA3 LTP. J. Neurosci. 17 (1997) 5196-5205
27. Ehlers M.D. Synapse structure: glutamate receptors connected by the shanks. Curr. Biol. 9 (1999) R848-R850
28. Alagarsamy S., et al. Activation of NMDA receptors reverses desensitization of mGluR5 in native and recombinant systems. Nat. Neurosci. 2 (1999) 234-240
29. Alagarsamy S., et al. NMDA-induced potentiation of mGluR5 is mediated by activation of protein phosphatase 2B/calcineurin. Neuropharmacology 49 Suppl. 1 (2005) 135-145
30. Brody S.A., et al. Assessment of a prepulse inhibition deficit in a mutant mouse lacking mGlu5 receptors. Mol. Psychiatry 9 (2004) 35-41
31. Kinney G.G., et al. Metabotropic glutamate subtype 5 receptors modulate locomotor activity and sensorimotor gating in rodents. J. Pharmacol. Exp. Ther. 306 (2003) 116-123
32. Campbell U.C., et al. The mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) potentiates PCP-induced cognitive deficits in rats. Psychopharmacology (Berl.) 175 (2004) 310-318
33. Conn, P.J. et al. Allosteric modulators of GPCRs as a novel approach for treatment of CNS disorders. Nat. Rev. Drug Discov. (in press)
34. Conn P.J., and Pin J.P. Pharmacology and functions of metabotropic glutamate receptors. Annu. Rev. Pharmacol. Toxicol. 37 (1997) 205-237
35. Chen Y., and Conn P.J. mGluR5 positive allosteric modulators. Drugs Future 33 (2008) 355-360
36. Lindsley C.W., et al. Discovery of positive allosteric modulators for the metabotropic glutamate receptor subtype 5 from a series of N-(1,3-diphenyl-1H- pyrazol-5-yl)benzamides that potentiate receptor function in vivo. J. Med. Chem. 47 (2004) 5825-5828
37. O'Brien J.A., et al. A family of highly selective allosteric modulators of the metabotropic glutamate receptor subtype 5. Mol. Pharmacol. 64 (2003) 731-740
38. O'Brien J.A., et al. A novel selective allosteric modulator potentiates the activity of native metabotropic glutamate receptor subtype 5 in rat forebrain. J. Pharmacol. Exp. Ther. 309 (2004) 568-577
39. Kinney G.G., et al. 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 (2005) 199-206
40. Zhao Z., et al. Challenges in the development of mGluR5 positive allosteric modulators: the discovery of CPPHA. Bioorg. Med. Chem. Lett. 17 (2007) 1386-1391
41. Chen Y., et al. 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 (2007) 1389-1398
42. de Paulis T., et al. Substituent effects of N-(1,3-diphenyl-1 H-pyrazol-5-yl) benzamides on positive allosteric modulation of the metabotropic glutamate-5 receptor in rat cortical astrocytes. J. Med. Chem. 49 (2006) 3332-3344
43. Rodriguez A., et al. 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 (2005) 1793-1802
44. Chen Y., et al. 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 (2008) 909-918
45. Zhang Y., et al. Allosteric potentiators of metabotropic glutamate receptor subtype 5 have differential effects on different signaling pathways in cortical astrocytes. J. Pharmacol. Exp. Ther. 315 (2005) 1212-1219
46. Ayala J.E., et al. Group III mGluR regulation of synaptic transmission at the SC-CA1 synapse is developmentally regulated. Neuropharmacology 54 (2008) 804-814
47. Lecourtier L., et al. Positive allosteric modulation of metabotropic glutamate 5 (mGlu5) receptors reverses N-methyl-D-aspartate antagonist-induced alteration of neuronal firing in prefrontal cortex. Biol. Psychiatry 62 (2007) 739-746
48. Darrah J.M., et al. Interaction of N-methyl-D-aspartate and group 5 metabotropic glutamate receptors on behavioral flexibility using a novel operant set-shift paradigm. Behav. Pharmacol. 19 (2008) 225-234
49. Epping-Jordan M.P., et al. In vivo characterization of mGluR5 positive allosteric modulators as novel treatments for schizophrenia and cognitive dysfunction. Neuropharmacology 49 Suppl. 1 (2005) 243
50. Schoepp D.D., and Marek G.J. Preclinical pharmacology of mGlu2/3 receptor agonists: novel agents for schizophrenia? Curr. Drug Targets CNS Neurol. Disord. 1 (2002) 215-225
51. Patil S.T., et al. Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized phase 2 clinical trial. Nat. Med. 13 (2007) 1102-1107
52. Moghaddam B., and Adams B.W. Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats. Science 281 (1998) 1349-1352
53. Marek G.J., et al. Physiological antagonism between 5-hydroxytryptamine(2A) and group II metabotropic glutamate receptors in prefrontal cortex. J. Pharmacol. Exp. Ther. 292 (2000) 76-87
54. Galici R., et al. 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. 315 (2005) 1181-1187
55. Fell M.J., et al. 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. 326 (2008) 209-217
56. Spooren W.P., et al. Lack of effect of LY314582 (a group 2 metabotropic glutamate receptor agonist) on phencyclidine-induced locomotor activity in metabotropic glutamate receptor 2 knockout mice. Eur. J. Pharmacol. 397 (2000) R1-R2
57. Johnson M.P., et al. 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. 46 (2003) 3189-3192
58. Cube R.V., et al. 3-(2-Ethoxy-4-{4-[3-hydroxy-2-methyl-4-(3-methylbutanoyl)phenoxy]butoxy}ph enyl)propanoic acid: a brain penetrant allosteric potentiator at the metabotropic glutamate receptor 2 (mGluR2). Bioorg. Med. Chem. Lett. 15 (2005) 2389-2393
59. Galici R., et al. 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 (2006) 173-185
60. Pinkerton A.B., et al. Allosteric potentiators of the metabotropic glutamate receptor 2 (mGlu2). Part 3: Identification and biological activity of indanone containing mGlu2 receptor potentiators. Bioorg. Med. Chem. Lett. 15 (2005) 1565-1571
61. Schaffhauser H., et al. Pharmacological characterization and identification of amino acids involved in the positive modulation of metabotropic glutamate receptor subtype 2. Mol. Pharmacol. 64 (2003) 798-810
62. Rowe B.A., et al. 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 (2008) 240-251
63. Bennyworth M., et al. A selective positive allosteric modulator of metabotropic glutamate receptor subtype 2 blocks a hallucinogenic drug model of psychosis. Mol. Pharmacol. 72 (2007) 477-484
64. Poisik O., et al. Metabotropic glutamate receptor 2 modulates excitatory synaptic transmission in the rat globus pallidus. Neuropharmacology 49 (2005) 135-145
65. Govek S.P., et al. Benzazoles as allosteric potentiators of metabotropic glutamate receptor 2 (mGluR2): efficacy in an animal model for schizophrenia. Bioorg. Med. Chem. Lett. 15 (2005) 4068-4072