Synthesis of GABAA receptor agonists and evaluation of their α-subunit selectivity and orientation in the GABA binding site

Journal of Medicinal Chemistry

Volumn 51, Issue 15, 2008, Pages 4430-4448

  Jansen, Michaela ^a,b   Rabe, Holger ^a   Strehle, Axelle ^a,c   Dieler, Sandra ^a   Debus, Fabian ^a   Dannhardt, Gerd ^a   Akabas, Myles H ^b   Lüddens, Hartmut ^a  

^a JOHANNES GUTENBERG UNIVERSITY   (Germany)

^b ALBERT EINSTEIN COLLEGE OF MEDICINE   (United States)

^c UNIVERSITÉ DE STRASBOURG   (France)

Author keywords

[No Author keywords available]

Indexed keywords

1 BENZYL 4[1,3,4]OXADIAZOLE 2YL PIPERIDINE; 4 (5 METHYL[1,3,4]OXADIAZOL 2 YL)PIPERIDINE; 4 AMINOBUTYRIC ACID A RECEPTOR STIMULATING AGENT; 4 BENZYL 5 PIPERIDIN 4 YL 2,4 DIHYDRO[1,2,4]TRIAZOLE 3 ONE; 5 (1 AMINO ETHYL) 3H[1,3,4]OXADIAZOL 2 ONE; 5 (1 BENZYLPIPERIDIN 4 YL) 3H[1,3,4]OXADIAZOL 2 ONE; 5 (1 BENZYLPIPERIDIN 4YL) 3H[1,3,4]OXADIAZOLE 2 THIONE; 5 (1 METHYLPIPERIDIN 4 YL) 3H[1,3,4]OXADIAZOL 2 ONE; 5 (1 METHYLPIPERIDIN 4YL) 3H[1,3,4]OXADIAZOLE 2 THIONE; 5 (2 AMINO ETHYL) 3H[1,3,4]OXADIAZOL 2 ONE; 5 (2 AMINO ETHYL) 3H[1,3,4]OXADIAZOL 2 THIONE; 5 AMINOMETHYL 3H[1,3,4]OXADIAZOL 2 ONE; 5 AMINOMETHYL 3H[1,3,4]OXADIAZOL 2 THIONE; 5 AMINOMETHYL 4 BENZYL 2,4 DIHYDRO[1,2,4]TRIAZOL 3 ONE; 5 CYCLOHEXYL 3H[1,3,4]OXADIAZOLE 2 ONE; 5 CYCLOHEXYL 3H[1,3,4]OXADIAZOLE 2 THIONE; 5 DIMETHYLAMINOMETHYL 3H[1,3,4]OXADIAZOL 2 ONE; 5 DIMETHYLAMINOMETHYL 3H[1,3,4]OXADIAZOL 2 THIONE; 5 METHYL 3H[1,3,4]OXADIAZOLE 2 ONE; 5 METHYL 3H[1,3,4]OXADIAZOLE 2 THIONE; 5 METHYLAMINOMETHYL 3H[1,3,4]OXADIAZOL 2 ONE; 5 METHYLAMINOMETHYL 3H[1,3,4]OXADIAZOL 2 THIONE; 5 PIPERIDIN 3 YL 3H[1,3,4]OXADIAZOL 2 ONE; 5 PIPERIDIN 3 YL 3H[1,3,4]OXADIAZOL 2 THIONE; 5 PIPERIDIN 4 YL 3H[1,3,4]OXADIAZOL 2 ONE; 5 PIPERIDIN 4 YL 3H[1,3,4]OXADIAZOL 2 THIONE; 5 PYROLLIDIN 2 YL 3H[1,3,4]OXADIAZOL 2 ONE; 5 PYROLLIDIN 2 YL 3H[1,3,4]OXADIAZOL 2 THIONE; DEXTRO 5 (1 AMINO ETHYL) 3H[1,3,4]OXADIAZOL 2 ONE; UNCLASSIFIED DRUG; UNINDEXED DRUG; 3 HYDROXY 5 (4 PIPERIDYL)ISOXAZOLE; 4 AMINOBUTYRIC ACID; 4 AMINOBUTYRIC ACID A RECEPTOR; 4,5,6,7-TETRAHYDROISOXAZOLO(5,4-C)PYRIDIN-3-OL; 5-(4-PIPERIDYL)ISOXAZOL-3-OL; GABOXADOL; ISOXAZOLE DERIVATIVE; MUSCIMOL; PIPERIDINE DERIVATIVE; PROTEIN SUBUNIT;

ALPHA CHAIN; ANIMAL CELL; ARTICLE; BINDING SITE; CELL STRAIN HEK293; CONCENTRATION RESPONSE; CONTROLLED STUDY; COVALENT BOND; DRUG ACTIVITY; DRUG BINDING; DRUG EFFICACY; DRUG POTENCY; DRUG SCREENING; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG SYNTHESIS; ELECTROPHYSIOLOGY; EMBRYO; FEASIBILITY STUDY; HUMAN; HUMAN CELL; IC 50; MODULATION; MOLECULAR MIMICRY; MUTAGENESIS; NONHUMAN; PATCH CLAMP; RECEPTOR UPREGULATION; SUBSTITUTION REACTION; ANIMAL; BRAIN; CELL LINE; CHEMICAL STRUCTURE; CHEMISTRY; DRUG EFFECT; DRUG POTENTIATION; FEMALE; GENETICS; METABOLISM; MUTATION; OOCYTE; RAT; STRUCTURE ACTIVITY RELATION; SYNTHESIS; XENOPUS LAEVIS;

ANIMALS; BINDING SITES; BRAIN; CELL LINE; ELECTROPHYSIOLOGY; FEMALE; GAMMA-AMINOBUTYRIC ACID; HUMANS; ISOXAZOLES; MODELS, MOLECULAR; MOLECULAR STRUCTURE; MUSCIMOL; MUTATION; OOCYTES; PATCH-CLAMP TECHNIQUES; PIPERIDINES; PROTEIN SUBUNITS; RATS; RECEPTORS, GABA-A; STRUCTURE-ACTIVITY RELATIONSHIP; XENOPUS LAEVIS;

EID: 49449108738     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm701562x     Document Type: Article

References (72)

1. Barnard, E. A.; Skolnick, P.; Olsen, R. W.; Mohler, H.; Sieghart, W.; Biggio, G.; Braestrup, C.; Bateson, A. N.; Langer, S. Z. International Union of Pharmacology. XV. Subtypes of gamma-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. Theta, a novel gamma-aminobutyric acid type A receptor subunit. Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 9891-9896.
3. Sinkkonen, S. T.; Hanna, M. C.; Kirkness, E. F.; Korpi, E. R. GABA(A) receptor epsilon and theta subunits display unusual structural variation between species and are enriched in the rat locus ceruleus. J. Neurosci. 2000, 20, 3588-3595.
4. Böhme, I.; Rabe, H.; Lüddens, H. Four amino acids in the alpha subunits determine the gamma-aminobutyric acid sensitivities of GABAA receptor subtypes. J. Biol. Chem. 2004, 279, 35193-35200.
5. Sieghart, W.; Sperk, G. Subunit composition, distribution and function of GABA(A) receptor subtypes. Curr. Top. Med. Chem. 2002, 2, 795-816.
6. A receptors to synaptic and extrasynaptic membranes of cerebellar granule cells. J. Neurosci. 1998, 18, 1693-1703.
7. Fritschy, J. M.; Johnson, D. K.; Mohler, H.; Rudolph, U. Independent assembly and subcellular targeting of GABA(A)-receptor subtypes demonstrated in mouse hippocampal and olfactory neurons in vivo. Neurosci. Lett. 1998, 249, 99-102.
8. Luddens, H.; Korpi, E. R. Biological function of GABAA/benzodiazepine receptor heterogeneity. J. Psychiatr. Res. 1995, 29, 77-94.
9. 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 alpha 5 subunit. Neuropharmacology 1996, 35, 1331-1335.
10. Skolnick, P.; Hu, R. J.; Cook, C. M.; Hurt, S. D.; Trometer, J. D.; Liu, R.; Huang, Q.; Cook, J. M. [3H]RY 80: A high-affinity, selective ligand for gamma-aminobutyric acidA receptors containing alpha-5 subunits. J. Pharmacol. Exp. Ther. 1997, 283, 488-493.
11. Luddens, H.; Pritchett, D. B.; Kohler, M.; Killisch, I.; Keinanen, K.; Monyer, H.; Sprengel, R.; Seeburg, P. H. Cerebellar GABAA receptor selective for a behavioural alcohol antagonist. Nature 1990, 346, 648-651.
12. A receptor channels: from subunits to functional entities. Curr. Opin. Neurobiol. 1992, 2, 263-269.
13. A receptor subunit for benzodiazepine pharmacology. Nature 1989, 338, 582-585.
14. A receptors. Trends Pharmacol. Sci. 1997, 18, 425-429.
15. Saarelainen, K. S.; Ranna, M.; Rabe, H.; Sinkkonen, S. T.; Moykkynen, T.; Uusi-Oukari, M.; Linden, A. M.; Luddens, H.; Korpi, E. R. Enhanced behavioral sensitivity to the competitive GABA agonist, gaboxadol, in transgenic mice over-expressing hippocampal extrasynaptic alpha6beta GABA(A) receptors. J. Neurochem. 2008, 105, 338-350.
16. Korpi, E. R.; Luddens, H. Furosemide interactions with brain GABAA receptors. Br. J. Pharmacol. 1997, 120, 741-748.
17. Korpi, E. R.; Kuner, T.; Seeburg, P. H.; Luddens, H. Selective antagonist for the cerebellar granule cell-specific gamma- aminobutyric acid type A receptor. Mol. Pharmacol. 1995, 47, 283-289.
18. Korpi, E. R.; Wong, G.; Luddens, H. Subtype specificity of gamma-aminobutyric acid type A receptor antagonism by clozapine. Naunyn-Schmiedebergs Arch. Pharmacol. 1995, 352, 365-373.
19. Barbee, J. G. Memory, benzodiazepines, and anxiety: integration of theoretical and clinical perspectives. J. Clin. Psychiatry 1993, 54 Suppl, 86-97, discussion 98-101.
20. Salinas, J. A.; McGaugh, J. L. Muscimol induces retrograde amnesia for changes in reward magnitude. Neurobiol. Learn. Mem. 1995, 63, 277-285.
21. Huang, Q.; Liu, R.; Zhang, P.; He, X.; McKernan, R.; Gan, T.; Bennett, D. W.; Cook, J. M. Predictive models for GABAA/benzodiazepine receptor subtypes: studies of quantitative structure-activity relationships for imidazobenzodiazepines at five recombinant GABAA/benzodiazepine receptor subtypes [alphaxbeta3gamma2 (x = 1-3, 5, and 6)] via comparative molecular field analysis. J. Med. Chem. 1998, 41, 4130-42.
22. 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 GABA(A)/BzR subtypes (alpha1beta3gamma2, alpha5beta3gamma2, and alpha6beta3gamma2) via a comprehensive ligand-mapping approach. J. Med. Chem. 2000, 43, 71-95.
23. Li, X.; Cao, H.; Zhang, C.; Furtmueller, R.; Fuchs, K.; Huck, S.; Sieghart, W.; Deschamps, J.; Cook, J. M. Synthesis, in vitro affinity, and efficacy of a bis-8-ethynyl-4H-imidazo[1,5a]-[1,4]benzodiazepine analogue, the first bivalent alpha5 subtype selective BzR/GABA(A) antagonist. J. Med. Chem. 2003, 46, 5567-5570.
24. Cook, J. B.; Foster, K. L.; Eiler, W. J., II; McKay, P. F.; Woods, J., II; Harvey, S. C.; Garcia, M.; Grey, C.; McCane, S.; Mason, D.; Cummings, R.; Li, X.; Cook, J. M.; June, H. L. Selective GABAA alpha5 benzodiazepine inverse agonist antagonizes the neurobehavioral actions of alcohol. Alcohol.: Clin. Exp. Res. 2005, 29, 1390-401.
25. Albaugh, P. A.; Marshall, L.; Gregory, J.; White, G.; Hutchison, A.; Ross, P. C.; Gallagher, D. W.; Tallman, J. F.; Crago, M.; Cassella, J. V. Synthesis and biological evaluation of 7,8,9,10-tetrahydroimidazo[1,2-c] pyrido[3,4-e]pyrimdin-5(6H)-ones as functionally selective ligands of the benzodiazepine receptor site on the GABA(A) receptor. J. Med. Chem. 2002, 45, 5043-5051.
26. Collins, I.; Moyes, C.; Davey, W. B.; Rowley, M.; Bromidge, F. A.; Quirk, K.; Atack, J. R.; McKernan, R. M.; Thompson, S. A.; Wafford, K.; Dawson, G. R.; Pike, A.; Sohal, B.; Tsou, N. N.; Ball, R. G.; Castro, J. L. 3-Heteroaryl-2-pyridones: benzodiazepine site ligands with functional delectivity for alpha 2/alpha 3-subtypes of human GABA(A) receptor-ion channels. J. Med. Chem. 2002, 45, 1887-1900.
27. Mitchinson, A.; Atack, J. R.; Blurton, P.; Carling, R. W.; Castro, J. L.; Curley, K. S.; Russell, M. G.; Marshall, G.; McKernan, R. M.; Moore, K. W.; Narquizian, R.; Smith, A.; Street, L. J.; Thompson, S. A.; Wafford, K. 2,5-Dihydropyrazolo[4,3-c]pyridin-3-ones: functionally selective benzodiazepine binding site ligands on the GABAA receptor. Bioorg. Med. Chem. Lett. 2004, 14, 3441-4.
28. Yasumatsu, H.; Morimoto, Y.; Yamamoto, Y.; Takehara, S.; Fukuda, T.; Nakao, T.; Setoguchi, M. The pharmacological properties of Y-23684, a benzodiazepine receptor partial agonist. Br. J. Pharmacol. 1994, 111, 1170-8.
29. Haefely, W.; Martin, J. R.; Schoch, P. Novel anxiolytics that act as partial agonists at benzodiazepine receptors. Trends Pharmacol. Sci. 1990, 11, 452-6.
30. Grunwald, C.; Rundfeldt, C.; Lankau, H. J.; Arnold, T.; Hofgen, N.; Dost, R.; Egerland, U.; Hofmann, H. J.; Unverferth, K. Synthesis, pharmacology, and structure-activity relationships of novel imidazolones and pyrrolones as modulators of GABAA receptors. J. Med. Chem. 2006, 49, 1855-1866.
31. Krogsgaard-Larsen, P.; Frolund, B.; Jorgensen, F. S.; Schousboe, A. GABAA receptor agonists, partial agonists, and antagonists. Design and therapeutic prospects. J. Med. Chem. 1994, 37, 2489-2505.
32. Rabe, H.; Picard, R.; Uusi-Oukari, M.; Hevers, W.; Lüddens, H.; Korpi, E. R. Coupling between agonist and chloride ionophore sites of the GABA(A) receptor: agonist/antagonist efficacy of 4-PIOL. Eur. J. Pharmacol. 2000, 409, 233-242.
33. Byberg, J. R.; Labouta, I. M.; Falch, E.; Hjeds, H.; Krogsgaard-Larsen, P.; Curtis, D. R.; Gynther, B. D. Synthesis and biological activity of a GABAA agonist which has no effect on benzodiazepine binding and of structurally related glycine antagonists. Drug Des. Delivery 1987, 1, 261-274.
34. Frolund, B.; Jensen, L. S.; Storustovu, S. I.; Stensbol, T. B.; Ebert, B.; Kehler, J.; Krogsgaard-Larsen, P.; Liljefors, T. 4-Aryl-5-(4-piperidyl)-3- isoxazolol GABAA antagonists: synthesis, pharmacology, and structure-activity relationships. J. Med. Chem. 2007, 50, 1988-1992.
35. Krehan, D.; Storustovu, S. I.; Liljefors, T.; Ebert, B.; Nielsen, B.; Krogsgaard-Larsen, P.; Frolund, B. Potent 4-arylalkyl-substituted 3-isothiazolol GABA(A) competitive/noncompetitive antagonists: synthesis and pharmacology. J. Med. Chem. 2006, 49, 1388-1396.
36. Frolund, B.; Jensen, L. S.; Guandalini, L.; Canillo, C.; Vestergaard, H. T.; Kristiansen, U.; Nielsen, B.; Stensbol, T. B.; Madsen, C.; Krogsgaard-Larsen, P.; Liljefors, T. Potent 4-aryl- or 4-arylalkyl-substituted 3-isoxazolol GABA(A) antagonists: synthesis, pharmacology, and molecular modeling. J. Med. Chem. 2005, 48, 427-439.
37. Frolund, B.; Tagmose, L.; Jorgensen, A. T.; Kristiansen, U.; Stensbol, T. B.; Liljefors, T.; Krogsgaard-Larsen, P. Design and synthesis of a new series of 4-alkylated 3-isoxazolol GABA A antagonists. Eur. J. Med. Chem. 2003, 38, 447-449.
38. Mortensen, M.; Frolund, B.; Jorgensen, A. T.; Liljefors, T.; Krogsgaard-Larsen, P.; Ebert, B. Activity of novel 4-PIOL analogues at human alpha 1 beta 2 gamma 2S GABA(A) receptors-correlation with hydrophobicity. Eur. J. Pharmacol. 2002, 451, 125-132.
39. Frolund, B.; Jorgensen, A. T.; Tagmose, L.; Stensbol, T. B.; Vestergaard, H. T.; Engblom, C.; Kristiansen, U.; Sanchez, C.; Krogsgaard-Larsen, P.; Liljefors, T. Novel class of potent 4-arylalkyl substituted 3-isoxazolol GABA(A) antagonists: synthesis, pharmacology, and molecular modeling. J. Med. Chem. 2002, 45, 2454-2468.
40. Frolund, B.; Kristiansen, U.; Brehm, L.; Hansen, A. B.; Krogsgaard-Larsen, P.; Falch, E. Partial GABAA receptor agonists. Synthesis and in vitro pharmacology of a series of nonannulated analogs of 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol. J. Med. Chem. 1995, 38, 3287-3296.
41. Akabas, M. H.; Stauffer, D. A.; Xu, M.; Karlin, A. Acetylcholine receptor channel structure probed in cysteine-substitution mutants. Science 1992, 258, 307-310.
42. A receptor channels. EMBO J. 1992, 11, 2017-2023.
43. Hartvig, L.; Lukensmejer, B.; Liljefors, T.; Dekermendjian, K. Two conserved arginines in the extracellular N-terminal domain of the GABA(A) receptor alpha(5) subunit are crucial for receptor function. J. Neurochem. 2000, 75, 1746-1753.
44. Westh-Hansen, S. E.; Witt, M. R.; Dekermendjian, K.; Liljefors, T.; Rasmussen, P. B.; Nielsen, M. Arginine residue 120 of the human GABAA receptor alpha 1, subunit is essential for GABA binding and chloride ion current gating. Neuroreport 1999, 10, 2417-2421.
45. 3H]muscimol photoaffinity substrate in the bovine gamma-aminobutyric acidA receptor alpha subunit. J. Biol. Chem. 1994, 269, 20380-20387.
46. Holden, J. H.; Czajkowski, C. Different residues in the GABAA receptor alpha 1T60-alpha 1K70 region mediate GABA and SR-95531 actions. J. Biol. Chem. 2002, 277, 18785-18792.
47. A receptor: evidence for a beta-strand. J. Neurosci. 1999, 19, 4847-4854.
48. Kloda, J. H.; Czajkowski, C. Agonist-, antagonist-, and benzodiazepine-induced structural changes in the alpha1 Met113-Leu132 region of the GABAA receptor. Mol. Pharmacol. 2007, 71, 483-493.
49. Celie, P. H.; van Rossum-Fikkert, S. E.; van Dijk, W. J.; Brejc, K.; Smit, A. B.; Sixma, T. K. Nicotine and carbamylcholine binding to nicotinic acetylcholine receptors as studied in AChBP crystal structures. Neuron 2004, 41, 907-914.
50. 13C NMR Study of some Derivatives of 1,3,4-Oxadiazoles, 1,3,4-Thiadiazoles and Isosydnones. Org. Magn. Res. 1982, 18, 159-164.
51. Roberts, D. D.; Lewis, S. D.; Ballou, D. P.; Olson, S. T.; Shafer, J. A. Reactivity of small thiolate anions and cysteine-25 in papain towards methylmethanethiosulfonate. Biochemistry 1986, 25, 5595-5601.
52. 2+ binding site in the channel of alpha1beta1 gamma-aminobutyric acid A receptors. Mol. Pharmacol. 1998, 53, 870-877.
53. Baumann, S. W.; Baur, R.; Sigel, E. Subunit arrangement of gamma-aminobutyric acid type A receptors. J. Biol. Chem. 2001, 276, 36275-36280.
54. Frolund, B.; Tagmose, L.; Liljefors, T.; Stensbol, T. B.; Engblom, C.; Kristiansen, U.; Krogsgaard-Larsen, P. A novel class of potent 3-isoxazolol GABA(A) antagonists: design, synthesis, and pharmacology. J. Med. Chem. 2000, 43, 4930-4833.
55. Krogsgaard-Larsen, P.; Mikkelsen, H.; Jacobsen, P.; Falch, E.; Curtis, D. R.; Peet, M. J.; Leah, J. D. 4,5,6,7-Tetrahydroisothiazolo[5,4-c] pyridin-3-ol and related analogues of THIP. Synthesis and biological activity. J. Med. Chem. 1983, 26, 895-900.
56. Brejc, K.; van Dijk, W. J.; Smit, A. B.; Sixma, T. K. The 2.7 A structure of AChBP, homologue of the ligand-binding domain of the nicotinic acetylcholine receptor. Novartis Found. Symp. 2002, 245, 22-29, discussion 29-32, 165-168.
57. Cromer, B. A.; Morton, C. J.; Parker, M. W. Anxiety over GABA(A) receptor structure relieved by AChBP. Trends Biochem. Sci. 2002, 27, 280-7.
58. Brejc, K.; van Dijk, W. J.; Klaassen, R. V.; Schuurmans, M.; van Der Oost, J.; Smit, A. B.; Sixma, T. K. Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors. Nature 2001, 411, 269-276.
59. Wagner, D. A.; Czajkowski, C. Structure and dynamics of the GABA binding pocket: A narrowing cleft that constricts during activation. J. Neurosci. 2001, 21, 67-74.
60. Jin, R.; Banke, T. G.; Mayer, M. L.; Traynelis, S. F.; Gouaux, E. Structural basis for partial agonist action at ionotropic glutamate receptors. Nat. Neurosci. 2003, 6, 803-810.
61. Aboul-Enein, M. N.; Azzouny, A. A.; Abdallah, N. A.; El-Shabrawy Makhlouf, A. A.; Werner, W. Synthesis of Certain 5-Piperidyl-1,3,4-Oxadiazol- 2(3H)-ones and -2(3H)-thiones having Nonulcerogenic, Antiinflammatory and Analgesic Activities. Sci. Pharm. 1995, 63, 175-190.
62. Bentley, K. W.; Burton, M.; Uff, B. C. 1,3,4-Oxadiazol-2(3H)-one Formation from N-Acylaminobiurets and Related Compounds and from 5-Benzyl 3-Acyl(thiocarbazates). J. Chem. Soc., Perkin Trans. 1 1982, 9, 2019-2021.
63. Dornow, A.; K., B. Notiz über die Darstellung von 1.3.4-Oxadiazolon-(5) und seinen C2-alkylierten Derivaten. Chem. Ber. 1949, 82, 121-123.
64. Hoggarth, E. 2-Benzoyldithiocarbazinic Acid and Related Compounds. J. Chem. Soc., Perkin Trans. 1 1952, 4811-4817.
65. Horning, D. E.; Muchowski, J. M. Five-membered Heterocyclic Thiones Part I. 1,3,4-Oxadiazol-2-thione. Can. J. Chem. 1972, 50, 3079-3083.
66. Korpi, E. R.; Luddens, H. Regional gamma-aminobutyric acid sensitivity of t- butylbicyclophosphoro[35S]thionate binding depends on gamma-aminobutyric acidA receptor alpha subunit. Mol. Pharmacol. 1993, 44, 87-92.
67. Luddens, H.; Korpi, E. R. GABA antagonists differentiate between recombinant GABAA/benzodiazepine receptor subtypes. J. Neurosci. 1995, 15, 6957-6962.
68. Pritchett, D. B.; Seeburg, P. H. Gamma-aminobutyric acidA receptor alpha 5-subunit creates novel type II benzodiazepine receptor pharmacology. J. Neurochem. 1990, 54, 1802-1804.
69. Hamill, O. P.; Marty, A.; Neher, E.; Sakmann, B.; Sigworth, F. J. Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflugers Arch. 1981, 391, 85-100.
70. A receptor pore-lining M2 segment. Nat. Neurosci. 2001, 4, 477-485.
71. Schwede, T.; Kopp, J.; Guex, N.; Peitsch, M. C. SWISS-MODEL: An automated protein homology-modeling server. Nucleic Acids Res. 2003, 31, 3381-3385.
72. Bali, M.; Akabas, M. H. Defining the propofol binding site location on the GABAA receptor. Mol. Pharmacol. 2004, 65, 68-76.