An orally bioavailable, functionally selective inverse agonist at the benzodiazepine site of GABAA α5 receptors with cognition enhancing properties

Journal of Medicinal Chemistry

Volumn 47, Issue 24, 2004, Pages 5829-5832

  Chambers, Mark S ^a   Atack, John R ^a   Carling, Robert W ^a   Collinson, Neil ^a   Cook, Susan M ^a   Dawson, Gerard R ^a   Ferris, Pushpindar ^a   Hobbs, Sarah C ^a   O'Connor, Desmond ^a   Marshall, George ^a   Rycroft, W ^a   MacLeod, Angus M ^a  

^a NEUROSCIENCE RESEARCH CENTRE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

3 TERT BUTYL 7 (5 METHYLISOXAZOL 3 YL) 2 (1 METHYL 1H 1,2,4 TRIAZOL 5 YLMETHOXY)PYRAZOLO[1,5 D][1,2,4]TRIAZINE; 4 AMINOBUTYRIC ACID A RECEPTOR STIMULATING AGENT; 4 ETHYL 6,7 DIMETHOXY BETA CARBOLINE 3 CARBOXYLIC ACID METHYL ESTER; BENZODIAZEPINE DERIVATIVE; DIAZEPAM; L 655708; N METHYL BETA CARBOLINE 3 CARBOXAMIDE; NOOTROPIC AGENT; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANXIETY; ARTICLE; COGNITION; CONTROLLED STUDY; DOSE RESPONSE; DRUG BINDING SITE; DRUG BIOAVAILABILITY; DRUG PENETRATION; DRUG RECEPTOR BINDING; DRUG SELECTIVITY; DRUG SYNTHESIS; EPILEPTOGENESIS; LEARNING; MAZE TEST; MEMORY; MICHAELIS CONSTANT; NONHUMAN; RAT; RECEPTOR OCCUPANCY; TASK PERFORMANCE; TOXICITY TESTING;

ADMINISTRATION, ORAL; ANIMALS; BINDING SITES; BIOLOGICAL AVAILABILITY; COGNITION; DOGS; ISOXAZOLES; MAZE LEARNING; MICE; NOOTROPIC AGENTS; PATCH-CLAMP TECHNIQUES; PROTEIN SUBUNITS; RADIOLIGAND ASSAY; RATS; RECEPTORS, GABA-A; TRIAZINES;

EID: 8644282797     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm040863t     Document Type: Article

References (41)

1. A receptors: Classification on the basis of subunit structure and receptor function. Pharmacol. Rev. 1998, 50, 291-313.
2. Bonnert, T. P.; McKernan, R. M.; Farrar, S.; Le Bourdelles, B.; Heavens, R. P.; Smith, D. W.; Hewson, L.; Rigby, M. R.; Sirinathsinghji, D. J.; Brown, N.; Wafford, K. A.; Whiting, P. J. θ, a novel γ-aminobutyric acid type A receptor subunit. Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 9891-9896.
3. Farrar, S. J.; Whiting, P. J.; Bonnert, T. P.; McKernan, R. M. Stoichiometry of a ligand-gated ion channel determined by fluorescence energy transfer. J. Biol. Chem. 1999, 274, 10100-10104.
4. A-receptor subtypes really occur in the brain? Trends Neurosci. 1996, 19, 139-143.
5. Olsen, R. W.; Venter J. C. Benzodiazepine/GABA receptors and chloride channels: Structural and functional properties; Alan R. Liss Inc.: New York, 1986.
6. Cole, S. O. Effects of benzodiazepines on acquisition and performance: A critical assessment. Neurosci. Biobehav. Rev. 1986, 10, 265-272.
7. Ghoneim, M. M.; Mewaldt, S. P. Benzodiazepines and human memory: A review Anaesthesiology 1990, 72, 926-938.
8. Hagen, T. J.; Guzman, F.; Schultz, C.; Cook, J. M.; Skolnick, P.; Shannon, H. E. Synthesis of 3,6-disubstituted β-carbolines which possess either benzodiazepine antagonist or agonist activity. Heterocycles 1986, 24, 2845-2855.
9. A/benzodiazepine receptor subtype. Med. Chem. Res. 1995, 5, 700-709.
10. McNamara, R. K.; Skelton, R. W. Benzodiazepine receptor antagonists flumazenil and CGS 8216 and inverse agonist β-CCM enhance spatial learning in the rat: Dissociation from anxiogenic actions. Psychobiology 1993, 21 (2), 101-108.
11. Dorow, R.; Horowski, R.; Paschelke, G.; Amin, M.; Braestrup, C. Severe anxiety induced by FG 7142, a β-carboline ligand for benzodiazepine receptors. Lancet 1983, 2, 98-99.
12. Petersen, E. N. DMCM: A potent convulsive benzodiazepine receptor ligand. Eur. J. Pharmacol 1983, 94, 117-124.
13. Little, H. J.; Nutt, D. J.; Taylor, S. C. Acute and chronic effects of the benzodiazepine receptor ligand FG 7142: proconvulsant properties and kindling. Br. J. Pharmacol. 1984, 83, 951-958.
14. Sarter, M.; Bruno, J. P.; Berntson, G. G. Psychotogenic properties of benzodiazepine receptor inverse agonists. Psychopharmacology 2001, 156, 1-13.
15. A receptor subtypes. Nature 1999, 401, 796-800.
16. Low, K.; Crestani, F.; Keist, R.; Benke, D.; Brunig, I.; Benson, J. A.; Fritschy, J.-M.; Rulicke, T.; Bluethmann, H.; Mohler, H.; Rudolph, U. Molecular and neuronal substrate for the selective attenuation of anxiety. Science 2000, 290, 131-134.
17. A receptor α1 subtype. Nat. Neurosci. 2000, 3, 587-592.
18. A receptor function and dissection of the pharmacology of benzodiazepines and general anesthetics through mouse genetics. Annu. Rev. Pharmacol. Toxicol. 2004, 44, 475-498.
19. A receptor. J. Neurosci. 2002, 22, 5572-5580.
20. A receptors. Proc. Natl. Am. Sci. 2002, 99, 8980-8985.
21. A receptors have α5β3γ2 pharmacological characteristics. Mol. Pharmacol. 1998, 54, 928-933.
22. A receptor subtypes. Pharmacol. Rev. 1995, 47, 181-234.
23. A/BzR subtypes (α1β3γ2, α5β3γ2 and α6β3γ2) via a comprehensive ligand-mapping approach. J. Med. Chem. 2000, 43, 71-95.
24. (b) Masciadri, R.; Thomas, A. W.; Wichmann, J. Preparation of 9H-imidazo[1,5-a][1,2,4]triazolo-[4,3-d][1,4]benzodiazepines as alpha5 subunit selective GABA A receptor inverse agonists. PCT Int. Appl. (F. Hoffmann-La Roche AG, Switz.) WO 02/040487, 2001.
25. Masciadri, R.; Thomas, A. W.; Wichmann, J. Imidazo[1,5-a]pyrimido[5,4-d]- benzodiazepine derivatives as GABA A receptor modulators. PCT Int. Appl. (F. Hoffmann-La Roche AG, Switz.) WO 02/094834, 2002.
26. A receptors which contain the α5 subunit. Neuropharmacology 1996, 35, 1331-1335.
27. A/BzR sites. Med. Chem. Res. 1999, 9, 71-88.
28. Chambers, M. S.; Atack, J. R.; Bromidge, F. A.; Broughton, H. B.; Cook, S.; Dawson, G. R.; Hobbs, S. C.; Maubach, K. A.; Reeve, A. J.; Seabrook, G. R.; Wafford, K.; MacLeod, A. M. 6,7-Dihydro-2-benzothiophen-4(5H)-ones: A novel class of GABA-A α5 receptor inverse agonists. J. Med. Chem. 2002, 45, 1176-1179.
29. A α5 receptor inverse agonist which enhances cognition. J. Med. Chem. 2003, 46, 2227-2240.
30. A α5 receptor inverse agonists as cognition enhancers. J. Med. Chem. 2004, 47, 2176-2179.
31. Zimmer, H.; Amer, A.; Van Pham, C.; Schmidt, D. G. On the synthesis of 4-alkoxy-2(5H)-furanones. J. Org. Chem. 1988, 53, 3368-3370.
32. Sung, K.; Lee, A.-R. Synthesis of [(4,5-disubstituted-4H-1,2,4-triazol-3- yl)thio]alkanoic acids and their analogues as potential antiinflammatory agents. J. Heterocycl. Chem. 1992, 29, 1101-1109.
33. Carling, W. R.; Mitchinson, A.; Moore, K. W.; Russell, M. G. N.; Scott, G.; Street, L. J. Pyrazolo-triazine derivatives as ligands for GABAreceptors. In PCT Int. Appl.; (Merck, Sharp & Dohme Limited). WO 00/23449.
34. A receptors. Mol. Pharmacol. 1993, 43, 970-975.
35. Radioligand binding and enzyme assays performed by MDS Pharma Services, PO Box 26-127, Taipei, Taiwan, R.O.C.
36. 2L subunits stably transfected into mouse fibroblast L-cells. Br. J. Pharmacol. 1992, 107, 732-737.
37. A receptors. Neuropsychopharmacology 1999, 20, 255-262.
38. Roberts, A. J.; Keith, L. D. Mineralocorticoid receptors mediate the enhancing effects of corticosterone on convulsion susceptibility in mice. J. Pharm. Exp. Ther. 1994, 270, 505-511.
39. Dawson, G. R.; Tricklebank, M. D. Use of the elevated plus maze in the search for novel anxiolytic agents. Trends Pharmacol. Sci. 1995, 16, 33-36.
40. Morris, R. Developments of a water-maze procedure for studying spatial learning in the rat. J. Neurosci. Methods 1984, 11, 47-60.
41. Steele, R. J.; Morris R. G. M. Delay-dependent impairment of a matching-to-place task with chronic and intrahippocampal infusion of the NMDA-antagonist D-AP5. Hippocampus 1999, 9, 118-136.