5832 Journal of Medicinal Chemistry, 2004, Vol. 47, No. 24
Letters
(21) Sur, C.; Quirk, K.; Dewar, D.; Atack, J. R.; McKernan, R. Rat
and human hippocampal R5 subunit-containing γ-aminobutyric
acidA receptors have R5â3γ2 pharmacological characteristics.
Mol. Pharmacol. 1998, 54, 928-933.
kindling potential of 13 compared to 15. Data demonstrating
the anxiogenic potential of 13 and 15 in the elevated plus maze
and associated occupancy of BZ sites on GABAA receptors. This
material is available free of charge via the Internet at
(22) Sieghart, W. Structure and pharmacology of γ-aminobutyric
acidA receptor subtypes. Pharmacol. Rev. 1995, 47, 181-234.
(23) (a) Huang, Q.; He, X.; Ma, C.; Liu, R.; Yu, S.; Dayer, C. A.;
Wenger, G. R.; McKernan, R.; Cook, J. M. Pharmacophore/
receptor models for GABAA/BzR subtypes (R1â3γ2, R5â3γ2 and
R6â3γ2) via a comprehensive ligand-mapping approach. J. Med.
Chem. 2000, 43, 71-95. (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. (c) 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.
(24) Quirk, K.; Blurton, P.; Fletcher, S.; Leeson, P.; Tang, F.; Mellilo,
D.; Ragan, C. I.; McKernan, R. M. [3H]L-655,708, a novel ligand
selective for the benzodiazepine site of GABAA receptors which
contain the R5 subunit. Neuropharmacology 1996, 35, 1331-
1335.
(25) Yu, S.; Ma, C.; He, X.; McKernan, R.; Cook, J. M. Studies in the
search for R5 subtype selective agonists for GABAA/BzR sites.
Med. Chem. Res. 1999, 9, 71-88.
(26) 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 R5 recep-
tor inverse agonists. J. Med. Chem. 2002, 45, 1176-1179.
(27) Chambers, M. S.; Atack, J. R.; Broughton, H. B.; Collinson, N.;
Cook, S.; Dawson, G. R.; Hobbs, S. C.; Marshall, G.; Maubach,
K. A.; Pillai, G. V.; Reeve, A. J.; MacLeod, A. M. Identification
of a novel, selective GABAA R5 receptor inverse agonist which
enhances cognition. J. Med. Chem. 2003, 46, 2227-2240.
(28) Sternfeld, F.; Carling, R. W.; Jelley, R. A.; Ladduwahetty, T.;
Merchant, K. J.; Moore, K. W.; Reeve, A. J.; Street, L. J.;
O’Connor, D.; Sohal, B.; Atack, J. R.; Cook, S.; Seabrook, G.;
Wafford, K.; Tattersall, F. D.; Collinson, N.; Dawson, G. R.;
Castro, J. L.; MacLeod, A. M. Selective, orally active γ-amino-
butyric acidA R5 receptor inverse agonists as cognition enhanc-
ers. J. Med. Chem. 2004, 47, 2176-2179.
(29) 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.
(30) 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.
(31) Carling, W. R.; Mitchinson, A.; Moore, K. W.; Russell, M. G. N.;
Scott, G.; Street, L. J. Pyrazolo-triazine derivatives as ligands
for GABA receptors. In PCT Int. Appl.; (Merck, Sharp & Dohme
Limited). WO 00/23449.
(32) Hadingham, K. L.; Wingrove, P.; Le Bourdelles, B.; Palmer, K.
J.; Ragan, C. I.; Whiting, P. J. Cloning of cDNA sequences
encoding human R2 and R3 γ-aminobutyric acidA receptor
subunits and characterization of the benzodiazepine pharma-
cology of recombinant R1-, R2-, R3- and R5-containing human
γ-aminobutyric acidA receptors. Mol. Pharmacol. 1993, 43, 970-
975.
(33) Radioligand binding and enzyme assays performed by MDS
Pharma Services, PO Box 26-127, Taipei, Taiwan, R.O.C.
(34) Horne, A. L.; Hadingham, K. L.; Macaulay, A. J.; Whiting, P.;
Kemp, J. A. The pharmacology of recombinant GABAA receptors
containing bovine R1, â1, γ2L subunits stably transfected into
mouse fibroblast L-cells. Br. J. Pharmacol. 1992, 107, 732-737.
(35) Atack, J. R.; Smith, A. J.; Emms, F.; McKernan, R. M. Regional
differences in the inhibition of mouse in vivo [3H]Ro 15-1788
binding reflect selectivity for R1 versus R2 and R3 subunit-
containing GABAA receptors. Neuropsychopharmacology 1999,
20, 255-262.
(36) Roberts, A. J.; Keith, L. D. Mineralocorticoid receptors mediate
the enhancing effects of corticosterone on convulsion susceptibil-
ity in mice. J. Pharm. Exp. Ther. 1994, 270, 505-511.
(37) 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.
References
(1) Barnard, E. A.; Skolnick, P.; Olsen, R. W.; Mohler, H.; Sieghart,
W.; Biggio, G.; Braestrup, C.; Bateson, A. N.; Langer, S. Z.
Subtypes of γ-aminobutyric acidA 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) McKernan, R. M.; Whiting, P. J. Which GABAA-receptor sub-
types 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 â-carbolines which
possess either benzodiazepine antagonist or agonist activity.
Heterocycles 1986, 24, 2845-2855.
(9) Liu, R.; Zhang, P.; McKernan, R. M.; Wafford, K.; Cook, J. M.
Synthesis of novel imidazobenzodiazepines selective for the
R5â2γ2 (Bz5) GABAA/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
â-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 â-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. Psychopharmacol-
ogy 2001, 156, 1-13.
(15) Rudolph, U.; Crestani, F.; Benke, D.; Brunig, I.; Benson, J. A.;
Fritschy, J.-M.; Martin, J. R.; Bluethmann, H.; Mohler, H.
Benzodiazepine actions mediated by specific γ-aminobutyric
acidA 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) McKernan, R. M.; Rosahl, T. W.; Reynolds, D. S.; Sur, C.;
Wafford, K. A.; Atack, J. R.; Farrar, S.; Myers, J.; Cook, G.;
Ferris, P.; Garrett, L.; Bristow, L.; Marshall, G.; Macaulay, A.;
Brown, N.; Howell, O.; Moore, K. W.; Carling, R. W.; Street, L.
J.; Castro, J. L.; Ragan, C. I.; Dawson, G. R.; Whiting, P. J.
Sedative but not anxiolytic properties of benzodiazepines are
mediated by the GABAA receptor R1 subtype. Nat. Neurosci.
2000, 3, 587-592.
(18) Rudolph, U.; Mohler, H. Analysis of GABAA receptor function
and dissection of the pharmacology of benzodiazepines and
general anesthetics through mouse genetics. Annu. Rev. Phar-
macol. Toxicol. 2004, 44, 475-498.
(19) Collinson, N.; Kuenzi, F. M.; Jarolimek, W.; Maubach, K. A.;
Cothliff, R.; Sur, C.; Smith, A.; Otu, F. M.; Howell, O.; Atack, J.
R.; McKernan, R. M.; Seabrook, G. R.; Dawson, G. R.; Whiting,
P. J.; Rosahl, T. W. Enhanced learning and memory and altered
GABAergic synaptic transmission in mice lacking the R5 subunit
of the GABAA receptor. J. Neurosci. 2002, 22, 5572-5580.
(20) Crestani, F.; Keist, R.; Fritschy, J.-M.; Benke, D.; Vogt, K.; Prut,
L.; Bluthmann, H.; Mohler, H.; Rudolph, U. Trace fear condi-
tioning involves hippocampal R5 GABAA receptors. Proc. Natl.
Am. Sci. 2002, 99, 8980-8985.
(38) Morris, R. Developments of a water-maze procedure for studying
spatial learning in the rat. J. Neurosci. Methods 1984, 11, 47-
60.
(39) Steele, R. J.; Morris R. G. M. Delay-dependent impairment of a
matching-to-place task with chronic and intrahippocampal infu-
sion of the NMDA-antagonist D-AP5. Hippocampus 1999, 9,
118-136.
JM040863T