Table of Contents Author Guidelines Submit a Manuscript
International Journal of Medicinal Chemistry
Volume 2015, Article ID 430248, 54 pages
http://dx.doi.org/10.1155/2015/430248
Review Article

A Review of the Updated Pharmacophore for the Alpha 5 GABA(A) Benzodiazepine Receptor Model

1Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USA
2Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
3Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS 39216, USA
4Department of Anesthesiology, Columbia University, New York, NY 10032, USA
5Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA
6Milwaukee Institute of Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USA

Received 11 February 2015; Revised 16 June 2015; Accepted 2 July 2015

Academic Editor: Hussein El-Subbagh

Copyright © 2015 Terry Clayton et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. P. S. Miller and A. R. Aricescu, “Crystal structure of a human GABAA receptor,” Nature, vol. 512, no. 7514, pp. 270–275, 2014. View at Publisher · View at Google Scholar · View at Scopus
  2. K. H. Backus, M. Arigoni, U. Drescher et al., “Stoichiometry of a recombinant GABAA receptor deduced from mutation-induced rectification,” Neuroreport, vol. 5, no. 3, pp. 285–288, 1993. View at Google Scholar
  3. H. Möhler, “Brain disorders and novel therapeutics,” Chimia, vol. 58, no. 10, pp. 718–720, 2004. View at Publisher · View at Google Scholar · View at Scopus
  4. H. Möhler, J.-M. Fritschy, F. Crestani, T. Hensch, and U. Rudolph, “Specific GABAA circuits in brain development and therapy,” Biochemical Pharmacology, vol. 68, no. 8, pp. 1685–1690, 2004. View at Publisher · View at Google Scholar · View at Scopus
  5. U. Rudolph and H. Möhler, “Analysis of GABAA receptor function and dissection of the pharmacology of benzodiazepines and general anesthetics through mouse genetics,” Annual Review of Pharmacology and Toxicology, vol. 44, pp. 475–498, 2004. View at Publisher · View at Google Scholar · View at Scopus
  6. D. J. Bailey, J. E. Tetzlaff, J. M. Cook, X. He, and F. J. Helmstetter, “Effects of hippocampal injections of a novel ligand selective for the α5β2γ2 subunits of the GABA/benzodiazepine receptor on Pavlovian conditioning,” Neurobiology of Learning and Memory, vol. 78, no. 1, pp. 1–10, 2002. View at Publisher · View at Google Scholar · View at Scopus
  7. T. M. DeLorey, R. C. Lin, B. McBrady et al., “Influence of benzodiazepine binding site ligands on fear-conditioned contextual memory,” European Journal of Pharmacology, vol. 426, no. 1-2, pp. 45–54, 2001. View at Publisher · View at Google Scholar · View at Scopus
  8. M. S. Chambers, J. R. Atack, F. A. Bromidge et al., “6,7-Dihydro-2-benzothiophen-4(5H)-ones: a novel class of GABA-A α5 receptor inverse agonists,” Journal of Medicinal Chemistry, vol. 45, no. 6, pp. 1176–1179, 2002. View at Publisher · View at Google Scholar · View at Scopus
  9. M. S. Chambers, J. R. Atack, H. B. Broughton et al., “Identification of a novel, selective GABAa α5 receptor inverse agonist which enhances cognition,” Journal of Medicinal Chemistry, vol. 46, no. 11, pp. 2227–2240, 2003. View at Publisher · View at Google Scholar · View at Scopus
  10. C. Sur, K. Quirk, D. Dewar, J. Atack, and R. Mckernan, “Rat and human hippocampal alpha 5 subunit-containing gamma-aminobutyric acid(A) receptors have alpha 5 beta 3 gamma 2 pharmacological characteristics,” Molecular Pharmacology, vol. 54, no. 5, pp. 928–933, 1998. View at Google Scholar · View at Scopus
  11. M. Sarter, “Taking stock of cognition enhancers,” Trends in Pharmacological Sciences, vol. 12, pp. 456–461, 1991. View at Publisher · View at Google Scholar · View at Scopus
  12. J. R. Atack, L. Alder, S. M. Cook, A. J. Smith, and R. M. McKernan, “In vivo labelling of α5 subunit-containing GABAA receptors using the selective radioligand [3H]L-655,708,” Neuropharmacology, vol. 49, no. 2, pp. 220–229, 2005. View at Publisher · View at Google Scholar · View at Scopus
  13. X. Y. Li, H. Cao, C. C. Zhang et al., “Synthesis, in vitro affinity, and efficacy of a bis 8-ethynyl-4H-imidazo[1,5α]-[1,4]benzodiazepine analogue, the first bivalent α5 subtype selective BzR/GABAA antagonist,” Journal of Medicinal Chemistry, vol. 46, no. 26, pp. 5567–5570, 2003. View at Publisher · View at Google Scholar · View at Scopus
  14. X. Li, Synthesis of selective ligands for GABAA/benzodiazepine receptors [Ph.D. thesis], University of Wisconsin-Milwaukee, Milwaukee, Wis, USA, 2004.
  15. A. H. Abadi, S. Lankow, B. Hoefgen, M. Decker, M. U. Kassack, and J. Lehmann, “Dopamine/serotonin receptor ligands, part III: synthesis and biological activities of 7,7′-alkylene-bis-6,7,8,9,14,15-hexahydro-5H-benz[d]indolo[2,3-g]azecines—application of the bivalent ligand approach to a novel type of dopamine receptor antagonist,” Archiv der Pharmazie, vol. 335, no. 8, pp. 367–373, 2002. View at Google Scholar
  16. W. Yin, F. Rivas, R. Furtmueller et al., “Synthesis, in-vitro affinity and efficacy of the first bivalent alpha 5 subtype selective BzR/GABA(A) antagonist,” in Proceedings of the 2004 Neuroscience Meeting, San Diego, Calif, USA, 2004.
  17. D. Han, F. Holger Försterling, X. Li et al., “A study of the structure-activity relationship of GABAA-benzodiazepine receptor bivalent ligands by conformational analysis with low temperature NMR and X-ray analysis,” Bioorganic and Medicinal Chemistry, vol. 16, no. 19, pp. 8853–8862, 2008. View at Publisher · View at Google Scholar · View at Scopus
  18. D. M. Han, F. H. Försterling, X. Y. Li, J. R. Deschamps, H. Cao, and J. M. Cook, “Determination of the stable conformation of GABAA-benzodiazepine receptor bivalent ligands by low temperature NMR and X-ray analysis,” Bioorganic & Medicinal Chemistry Letters, vol. 14, no. 6, pp. 1465–1469, 2004. View at Publisher · View at Google Scholar · View at Scopus
  19. C. C. Zhang, Structure Activity Relationships and Cytotoxic Activity of Analogs of Tryprostatin A and B. Preparation of Irreversible Inhibitors for Studies of Mechanism and Action. II. Pharmacophore Receptor Models of GABA(A)/BzR, University of Wisconsin-Milwaukee, Milwaukee, Wis, USA, 2004.
  20. R. Y. Liu, R. J. Hu, P. W. Zhang, P. Skolnick, and J. M. Cook, “Synthesis and pharmacological properties of novel 8-substituted imidazobenzodiazepines: high-affinity, selective probes for α5-containing GABAA receptors,” Journal of Medicinal Chemistry, vol. 39, no. 9, pp. 1928–1934, 1996. View at Publisher · View at Google Scholar · View at Scopus
  21. Q. Huang, X. H. He, C. R. Ma et al., “Pharmacophore/receptor models for GABAA/BzR subtypes (α1β3γ2, α5β3γ2, and α6β3γ2) via a comprehensive ligand-mapping approach,” Journal of Medicinal Chemistry, vol. 43, no. 1, pp. 71–95, 2000. View at Publisher · View at Google Scholar
  22. T. Clayton, Part I. Unified pharmacophore protein models of the benzodiazepine receptor subtypes. Part II. Subtype selective ligands for alpha5 Gaba(A) /BZ receptors [Ph.D. thesis], University of Wisconsin-Milwaukee, Milwaukee, Wis, USA, 2011.
  23. T. Clayton, J. L. Chen, M. Ernst et al., “An updated unified pharmacophore model of the benzodiazepine binding site on γ-aminobutyric acida receptors: correlation with comparative models,” Current Medicinal Chemistry, vol. 14, no. 26, pp. 2755–2775, 2007. View at Publisher · View at Google Scholar · View at Scopus
  24. M. M. Savić, T. Clayton, R. Furtmüller et al., “PWZ-029, a compound with moderate inverse agonist functional selectivity at GABA-A receptors containing alpha5 subunits, improves passive, but not active, avoidance learning in rats,” Brain Research, vol. 1208, pp. 150–159, 2008. View at Publisher · View at Google Scholar · View at Scopus
  25. M. Milić, T. Timić, S. Joksimović et al., “PWZ-029, an inverse agonist selective for α5 GABAA receptors, improves object recognition, but not water-maze memory in normal and scopolamine-treated rats,” Behavioural Brain Research, vol. 241, no. 1, pp. 206–213, 2013. View at Publisher · View at Google Scholar · View at Scopus
  26. J. K. Rowlett, C. A. Moran, T. Clayton, S. Rallapalli, B. Roth, and J. M. Cook, PWZ-029, An Inverse Agonist Selective for α5 Subunit Containing GABA(A) Receptors, Enhances Performance on an Executive Function Task in Monkeys, European Behavioral Pharmacology Society, Rome, Italy, 2009.
  27. F. M. Benes, B. Lim, D. Matzilevich, J. P. Walsh, S. Subburaju, and M. Minns, “Regulation of the GABA cell phenotype in hippocampus of schizophrenics and bipolars,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 24, pp. 10164–10169, 2007. View at Publisher · View at Google Scholar · View at Scopus
  28. L. M. Rimol, C. B. Hartberg, R. Nesvåg et al., “Cortical thickness and subcortical volumes in schizophrenia and bipolar disorder,” Biological Psychiatry, vol. 68, no. 1, pp. 41–50, 2010. View at Publisher · View at Google Scholar · View at Scopus
  29. C. Pantelis, D. Velakoulis, P. D. McGorry et al., “Neuroanatomical abnormalities before and after onset of psychosis: a cross-sectional and longitudinal MRI comparison,” The Lancet, vol. 361, no. 9354, pp. 281–288, 2003. View at Publisher · View at Google Scholar · View at Scopus
  30. S. A. Schobel, M. A. Kelly, C. M. Corcoran et al., “Anterior hippocampal and orbitofrontal cortical structural brain abnormalities in association with cognitive deficits in schizophrenia,” Schizophrenia Research, vol. 114, no. 1–3, pp. 110–118, 2009. View at Publisher · View at Google Scholar · View at Scopus
  31. S. A. Schobel, N. M. Lewandowski, C. M. Corcoran et al., “Differential targeting of the CA1 subfield of the hippocampal formation by schizophrenia and related psychotic disorders,” Archives of General Psychiatry, vol. 66, no. 9, pp. 938–946, 2009. View at Publisher · View at Google Scholar · View at Scopus
  32. A. P. Weiss, D. Goff, D. L. Schacter et al., “Fronto-hippocampal function during temporal context monitoring in schizophrenia,” Biological Psychiatry, vol. 60, no. 11, pp. 1268–1277, 2006. View at Publisher · View at Google Scholar · View at Scopus
  33. R. C. Wolf, A. Höse, K. Frasch, H. Walter, and N. Vasic, “Volumetric abnormalities associated with cognitive deficits in patients with schizophrenia,” European Psychiatry, vol. 23, no. 8, pp. 541–548, 2008. View at Publisher · View at Google Scholar · View at Scopus
  34. H. Moore, J. D. Jentsch, M. Ghajarnia, M. A. Geyer, and A. A. Grace, “A neurobehavioral systems analysis of adult rats exposed to methylazoxymethanol acetate on E17: implications for the neuropathology of schizophrenia,” Biological Psychiatry, vol. 60, no. 3, pp. 253–264, 2006. View at Publisher · View at Google Scholar · View at Scopus
  35. P. Flagstad, A. Mørk, B. Y. Glenthøj, J. Van Beek, A. T. Michael-Titus, and M. Didriksen, “Disruption of neurogenesis on gestational day 17 in the rat causes behavioral changes relevant to positive and negative schizophrenia symptoms and alters amphetamine-induced dopamine release in nucleus accumbens,” Neuropsychopharmacology, vol. 29, no. 11, pp. 2052–2064, 2004. View at Publisher · View at Google Scholar · View at Scopus
  36. D. J. Lodge and A. A. Grace, “Aberrant hippocampal activity underlies the dopamine dysregulation in an animal model of schizophrenia,” The Journal of Neuroscience, vol. 27, no. 42, pp. 11424–11430, 2007. View at Publisher · View at Google Scholar · View at Scopus
  37. D. J. Lodge, M. M. Behrens, and A. A. Grace, “A loss of parvalbumin-containing interneurons is associated with diminished oscillatory activity in an animal model of schizophrenia,” The Journal of Neuroscience, vol. 29, no. 8, pp. 2344–2354, 2009. View at Publisher · View at Google Scholar · View at Scopus
  38. K. M. Gill, D. J. Lodge, J. M. Cook, S. Aras, and A. A. Grace, “A novel α5GABAAR-positive allosteric modulator reverses hyperactivation of the dopamine system in the MAM model of schizophrenia,” Neuropsychopharmacology, vol. 36, no. 9, pp. 1903–1911, 2011. View at Publisher · View at Google Scholar · View at Scopus
  39. W. Zhang, K. F. Koehler, P. Zhang, and J. M. Cook, “Development of a comprehensive pharmacophore model for the benzodiazepine receptor,” Drug Design and Discovery, vol. 12, no. 3, pp. 193–248, 1995. View at Google Scholar · View at Scopus
  40. W. Zhang, H. Diaz-Arauzo, M. S. Allen, K. F. Koehler, and J. M. Cook, “Chemical and computer assisted development of the inclusive pharmacophore of benzodiazepine receptors,” in Studies in Medicinal Chemistry, M. I. Choudhary, Ed., p. 303, Harwood Academic Publishers, 1996. View at Google Scholar
  41. P. W. Zhang, W. J. Zhang, R. Y. Liu, B. Harris, P. Skolnick, and J. M. Cook, “Synthesis and SAR study of novel imidazobenzodiazepines at ‘diazepam-insensitive’ benzodiazepine receptors,” Journal of Medicinal Chemistry, vol. 38, no. 10, pp. 1679–1688, 1995. View at Google Scholar
  42. Q. Huang, E. D. Cox, T. Gan et al., “Studies of molecular pharmacophore/receptor models for GABA(A)/benzodiazepine receptor subtypes: binding affinities of substituted β-carbolines at recombinant α1β3γ2 subtypes and quantitative structure-activity relationship studies via a comparative molecular field analysis,” Drug Design and Discovery, vol. 16, no. 1, pp. 55–76, 1999. View at Google Scholar · View at Scopus
  43. D. Harris, T. Clayton, J. Cook et al., “Selective influence on contextual memory: physiochemical properties associated with selectivity of benzodiazepine ligands at GABAA receptors containing the α5 subunit,” Journal of Medicinal Chemistry, vol. 51, no. 13, pp. 3788–3803, 2008. View at Publisher · View at Google Scholar · View at Scopus
  44. D. Rüedi-Bettschen, J. K. Rowlett, S. Rallapalli, T. Clayton, J. M. Cook, and D. M. Platt, “Modulation of α5 subunit-containing GABAA receptors alters alcohol drinking by rhesus monkeys,” Alcoholism: Clinical and Experimental Research, vol. 37, no. 4, pp. 624–634, 2013. View at Publisher · View at Google Scholar · View at Scopus
  45. M. M. Savić, M. M. Milinković, S. Rallapalli et al., “The differential role of alpha1- and alpha5-containing GABAA receptors in mediating diazepam effects on spontaneous locomotor activity and water-maze learning and memory in rats,” International Journal of Neuropsychopharmacology, vol. 12, no. 9, pp. 1179–1193, 2009. View at Publisher · View at Google Scholar · View at Scopus
  46. X. Y. Li, C. R. Ma, X. H. He et al., “Studies in search of diazepam-insensitive subtype selective agents for GABAA/Bz receptors,” Medicinal Chemistry Research, vol. 11, no. 9, pp. 504–537, 2003. View at Google Scholar
  47. L. Duggan, M. Fenton, J. Rathbone, R. Dardennes, A. El-Dosoky, and S. Indran, “Olanzapine for schizophrenia,” Cochrane Database of Systematic Reviews, no. 2, Article ID CD001359, 2005. View at Google Scholar · View at Scopus
  48. J. A. Lieberman, T. S. Stroup, J. P. McEvoy et al., “Effectiveness of antipsychotic drugs in patients with chronic schizophrenia,” The New England Journal of Medicine, vol. 353, no. 12, pp. 1209–1223, 2005. View at Publisher · View at Google Scholar · View at Scopus
  49. K. Komossa, C. Rummel-Kluge, H. Hunger et al., “Olanzapine versus other atypical antipsychotics for schizophrenia,” Cochrane Database of Systematic Reviews, no. 3, Article ID CD006654, 2010. View at Google Scholar · View at Scopus
  50. K. Komossa, C. Rummel-Kluge, H. Hunger et al., “Zotepine versus other atypical antipsychotics for schizophrenia,” Cochrane Database of Systematic Reviews, no. 1, p. CD006628, 2010. View at Google Scholar · View at Scopus
  51. K. Komossa, C. Rummel-Kluge, H. Hunger et al., “Amisulpride versus other atypical antipsychotics for schizophrenia,” Cochrane Database of Systematic Reviews, no. 1, p. CD006624, 2010. View at Google Scholar · View at Scopus
  52. K. Komossa, C. Rummel-Kluge, F. Schmid et al., “Quetiapine versus other atypical antipsychotics for schizophrenia,” Cochrane Database of Systematic Reviews, no. 1, Article ID CD006625, 2010. View at Google Scholar · View at Scopus
  53. C. Sur, L. Fresu, O. Howell, R. M. McKernan, and J. R. Atack, “Autoradiographic localization of α5 subunit-containing GABA(A) receptors in rat brain,” Brain Research, vol. 822, no. 1-2, pp. 265–270, 1999. View at Publisher · View at Google Scholar · View at Scopus
  54. H. L. June, S. C. Harvey, K. L. Foster et al., “GABAA receptors containing α5 subunits in the CA1 and CA3 hippocampal fields regulate ethanol-motivated behaviors: an extended ethanol reward circuitry,” The Journal of Neuroscience, vol. 21, no. 6, pp. 2166–2177, 2001. View at Google Scholar · View at Scopus
  55. A. Lingford-Hughes, S. P. Hume, A. Feeney et al., “Imaging the GABA-benzodiazepine receptor subtype containing the alpha5-subunit in vivo with [11C]Ro15 4513 positron emission tomography,” Journal of Cerebral Blood Flow and Metabolism, vol. 22, no. 7, pp. 878–889, 2002. View at Google Scholar · View at Scopus
  56. B. Hutcheon, J. M. Fritschy, and M. O. Poulter, “Organization of GABAA receptor alpha-subunit clustering in the developing rat neocortex and hippocampus,” European Journal of Neuroscience, vol. 19, no. 9, pp. 2475–2487, 2004. View at Publisher · View at Google Scholar · View at Scopus
  57. B. Ramos, J. F. Lopez-Tellez, J. Vela et al., “Expression of α5 GABAA receptor subunit in developing rat hippocampus,” Developmental Brain Research, vol. 151, no. 1-2, pp. 87–98, 2004. View at Publisher · View at Google Scholar · View at Scopus
  58. S. K. Towers, T. Gloveli, R. D. Traub et al., “Alpha5 subunit-containing GABAA receptors affect the dynamic range of mouse hippocampal kainate-induced gamma frequency oscillations in vitro,” Journal of Physiology, vol. 559, no. 3, pp. 721–728, 2004. View at Publisher · View at Google Scholar · View at Scopus
  59. S. A. Heldt and K. J. Ressler, “Forebrain and midbrain distribution of major benzodiazepine-sensitive GABAA receptor subunits in the adult C57 mouse as assessed with in situ hybridization,” Neuroscience, vol. 150, no. 2, pp. 370–385, 2007. View at Publisher · View at Google Scholar · View at Scopus
  60. C. Papatheodoropoulos and E. Koniaris, “α5GABAA receptors regulate hippocampal sharp wave-ripple activity in vitro,” Neuropharmacology, vol. 60, no. 4, pp. 662–673, 2011. View at Publisher · View at Google Scholar · View at Scopus
  61. K. M. Gill, J. M. Cook, M. M. Poe, and A. A. Grace, “Prior antipsychotic drug treatment prevents response to novel antipsychotic agent in the methylazoxymethanol acetate model of schizophrenia,” Schizophrenia Bulletin, vol. 40, no. 2, pp. 341–350, 2014. View at Publisher · View at Google Scholar · View at Scopus
  62. C. C. Kaczorowski and J. F. Disterhoft, “Memory deficits are associated with impaired ability to modulate neuronal excitability in middle-aged mice,” Learning and Memory, vol. 16, no. 6, pp. 362–366, 2009. View at Publisher · View at Google Scholar · View at Scopus
  63. C. C. Kaczorowski, E. Sametsky, S. Shah, R. Vassar, and J. F. Disterhoft, “Mechanisms underlying basal and learning-related intrinsic excitability in a mouse model of Alzheimer's disease,” Neurobiology of Aging, vol. 32, no. 8, pp. 1452–1465, 2011. View at Publisher · View at Google Scholar · View at Scopus
  64. C. C. Kaczorowski, S. J. Davis, and J. R. Moyer Jr., “Aging redistributes medial prefrontal neuronal excitability and impedes extinction of trace fear conditioning,” Neurobiology of Aging, vol. 33, no. 8, pp. 1744–1757, 2012. View at Publisher · View at Google Scholar · View at Scopus
  65. S. I. Rallapalli, Synthesis of Agents to Enhance Cognition. II. Synthesis of Indole Alkaloids, University of Wisconsin-Milwaukee, 2014.
  66. P. J. Barnes, “Biochemistry of asthma,” Trends in Biochemical Sciences, vol. 16, pp. 365–369, 1991. View at Publisher · View at Google Scholar · View at Scopus
  67. D. W. Cockcroft, “Clinical concerns with inhaled β2-agonists: adult asthma,” Clinical Reviews in Allergy and Immunology, vol. 31, no. 2-3, pp. 197–208, 2006. View at Publisher · View at Google Scholar · View at Scopus
  68. R. W. Morton, M. L. Everard, and H. E. Elphick, “Adherence in childhood asthma: the elephant in the room,” Archives of Disease in Childhood, vol. 99, no. 10, pp. 949–953, 2014. View at Publisher · View at Google Scholar · View at Scopus
  69. N. S. Jentzsch, P. Camargos, E. S. C. Sarinho, and J. Bousquet, “Adherence rate to beclomethasone dipropionate and the level of asthma control,” Respiratory Medicine, vol. 106, no. 3, pp. 338–343, 2012. View at Publisher · View at Google Scholar · View at Scopus
  70. E. K. Chu and J. M. Drazen, “Asthma: one hundred years of treatment and onward,” The American Journal of Respiratory and Critical Care Medicine, vol. 171, no. 11, pp. 1202–1208, 2005. View at Publisher · View at Google Scholar · View at Scopus
  71. G. Gallos, N. R. Gleason, Y. Zhang et al., “Activation of endogenous GABAA channels on airway smooth muscle potentiates isoproterenol-mediated relaxation,” The American Journal of Physiology—Lung Cellular and Molecular Physiology, vol. 295, no. 6, pp. L1040–L1047, 2008. View at Publisher · View at Google Scholar · View at Scopus
  72. K. Mizuta, D. Xu, Y. Pan et al., “GABAA receptors are expressed and facilitate relaxation in airway smooth muscle,” The American Journal of Physiology—Lung Cellular and Molecular Physiology, vol. 294, no. 6, pp. L1206–L1216, 2008. View at Publisher · View at Google Scholar · View at Scopus
  73. M. M. Savić, T. Clayton, R. Furtmüller et al., “PWZ-029, a compound with moderate inverse agonist functional selectivity at GABAA receptors containing α5 subunits, improves passive, but not active, avoidance learning in rats,” Brain Research, vol. 1208, pp. 150–159, 2008. View at Publisher · View at Google Scholar · View at Scopus
  74. M. M. Savić, S. Huang, R. Furtmüller et al., “Are GABAA receptors containing alpha5 subunits contributing to the sedative properties of benzodiazepine site agonists?” Neuropsychopharmacology, vol. 33, no. 2, pp. 332–339, 2008. View at Publisher · View at Google Scholar · View at Scopus
  75. G. Gallos, G. T. Yocum, M. E. Siviski et al., “Selective targeting of the α5 subunit of GABAA receptors relaxes airway smooth muscle and inhibits cellular calcium handling,” American Journal of Physiology—Lung Cellular and Molecular Physiology, vol. 308, no. 9, pp. L931–L942, 2015. View at Publisher · View at Google Scholar
  76. M. S. Allen, Y.-C. Tan, M. L. Trudell et al., “Synthetic and computer-assisted analyses of the pharmacophore for the benzodiazepine receptor inverse agonist site,” Journal of Medicinal Chemistry, vol. 33, no. 9, pp. 2343–2357, 1990. View at Publisher · View at Google Scholar · View at Scopus
  77. M. S. Allen, T. J. Hagen, M. L. Trudell, P. W. Codding, P. Skolnick, and J. M. Cook, “Synthesis of novel 3-substituted β-carbolines as benzodiazepine receptor ligands: probing the benzodiazepine receptor pharmacophore,” Journal of Medicinal Chemistry, vol. 31, no. 9, pp. 1854–1861, 1988. View at Publisher · View at Google Scholar · View at Scopus
  78. H. Diaz-Arauzo, G. E. Evoniuk, P. Skolnick, and J. M. Cook, “The agonist pharmacophore of the benzodiazepine receptor. Synthesis of a selective anticonvulsant/anxiolytic,” Journal of Medicinal Chemistry, vol. 34, no. 5, pp. 1754–1756, 1991. View at Publisher · View at Google Scholar · View at Scopus
  79. H. Diaz-Arauzo, K. F. Koehler, T. J. Hagen, and J. M. Cook, “Synthetic and computer assisted analysis of the pharmacophore for agonists at benzodiazepine receptors,” Life Sciences, vol. 49, no. 3, pp. 207–216, 1991. View at Publisher · View at Google Scholar · View at Scopus
  80. W. J. Zhang, K. F. Koehler, B. Harris, P. Skolnick, and J. M. Cook, “Synthesis of benzo-fused benzodiazepines employed as probes of the agonist pharmacophore of benzodiazepine receptors,” Journal of Medicinal Chemistry, vol. 37, no. 6, pp. 745–757, 1994. View at Publisher · View at Google Scholar · View at Scopus
  81. M. L. Trudell, S. L. Lifer, Y.-C. Tan et al., “Synthesis of substituted 7,12-dihydropyrido[3,2-b:5,4-b′]diindoles: rigid planar benzodiazepine receptor ligands with inverse agonist/antagonist properties,” Journal of Medicinal Chemistry, vol. 33, no. 9, pp. 2412–2420, 1990. View at Publisher · View at Google Scholar · View at Scopus
  82. M. L. Trudell, A. S. Basile, H. E. Shannon, P. Skolnick, and J. M. Cook, “Synthesis of 7,12-dihydropyrido[3,4-b:5,4-b′]diindoles. A novel class of rigid, planar benzodiazepine receptor ligands,” Journal of Medicinal Chemistry, vol. 30, no. 3, pp. 456–458, 1987. View at Publisher · View at Google Scholar · View at Scopus
  83. M. J. Frisch, G. W. Trucks, M. Head-Gordon et al., Gaussian 92, Gaussian, Pittsburgh, Pa, USA, 1992, http://www.lct.jussieu.fr/manuels/Gaussian98/00000119.htm.
  84. M. L. I. Trudell, The synthesis and study of the pharmacologic activity of 7,12 dihydropyrido[3,2 b:5,4 b′]diindoles. A novel class of rigid, planar benzodiazepine receptor ligands. II. The total synthesis of the indole alkaloid, (±) suaveoline [Ph.D. thesis], University of Wisconsin-Milwaukee, Milwaukee, Wis, USA, 1989.
  85. W. Yin, S. Majumder, T. Clayton et al., “Design, synthesis, and subtype selectivity of 3,6-disubstituted β-carbolines at Bz/GABA(A)ergic receptors. SAR and studies directed toward agents for treatment of alcohol abuse,” Bioorganic and Medicinal Chemistry, vol. 18, no. 21, pp. 7548–7564, 2010. View at Publisher · View at Google Scholar · View at Scopus
  86. D. Han, F. H. Forsterling, X. Li, J. Deschamps, H. Cao, and J. M. Cook, “Study of the structure activity relationships of GABAA-benzodiazepine receptor ligands by low termperature NMR spectroscopy and X-ray analysis,” in Proceedings of the 227th ACS National Meeting, Anaheim, Calif, USA, March-April 2004.
  87. B. D. Fischer, S. C. Licata, H. Zhou et al., “Anxiolytic-like effects of 8-acetylene imidazobenzodiazepines in a rhesus monkey conflict procedure,” Neuropharmacology, vol. 59, no. 7-8, pp. 612–618, 2010. View at Publisher · View at Google Scholar · View at Scopus
  88. W. Haefely, E. Kyburz, M. Gerecke, and H. Mohler, “Recent advances in the molecular pharmacology of benzodiazepine receptors and in the structure—activity relationships of their agonist and antagonists,” in Advances in Drug Research, vol. 99, pp. 165–322, Academic Press, New York, NY, USA, 1985. View at Google Scholar
  89. R. I. Fryer, Z.-Q. Gu, and C.-G. Wang, “Synthesis of novel, substituted 4H-imidazo[1,5-a][1,4]benzodiazepines,” Journal of Heterocyclic Chemistry, vol. 28, no. 7, pp. 1661–1669, 1991. View at Publisher · View at Google Scholar · View at Scopus
  90. R. I. Fryer, P. Zhang, R. Rios, Z.-Q. Gu, A. S. Basile, and P. Skolnick, “Structure-activity relationship studies at the benzodiazepine receptor (Bzr)—a comparison of the substituent effects of pyrazoloquinolinone analogs,” Journal of Medicinal Chemistry, vol. 36, no. 11, pp. 1669–1673, 1993. View at Publisher · View at Google Scholar · View at Scopus
  91. F. M. Rivas, C. R. Edwankar, J. M. Cook et al., “Antiseizure activity of novel γ-aminobutyric acid (A) receptor subtype-selective benzodiazepine analogues in mice and rat models,” Journal of Medicinal Chemistry, vol. 52, no. 7, pp. 1795–1798, 2009. View at Publisher · View at Google Scholar · View at Scopus
  92. J. M. Cook, D. Han, X. He et al., “Anxiolytic agents with reduced sedative and ataxic effects,” 7119196 B2, 2006.
  93. J. M. Cook, H. Zhao, S. Huang, P. S. Sarma, and C. C. Zhang, “Stereospecific anxiolytic and anticonvulsant agents with reduced muscle-relaxant, sedative-hypnotic and ataxic effects,” US Patent 2006004945, 2007.
  94. R. I. Fryer, Comprehensive Medicinal Chemistry, vol. 99, Pergamon Press, Oxford, UK, 1989.
  95. H. O. Villar, M. F. Davies, G. H. Loew, and P. A. Maguire, “Molecular models for recognition and activation at the benzodiazepine receptor: a review,” Life Sciences, vol. 48, no. 7, pp. 593–602, 1991. View at Publisher · View at Google Scholar · View at Scopus
  96. H. O. Villar, E. T. Uyeno, L. Toll, W. Polgar, M. F. Davies, and G. H. Loew, “Molecular determinants of benzodiazepine receptor affinities and anticonvulsant activities,” Molecular Pharmacology, vol. 36, no. 4, pp. 589–600, 1989. View at Google Scholar · View at Scopus
  97. G. M. Crippen, “Distance geometry analysis of the benzodiazepine binding site,” Molecular Pharmacology, vol. 22, no. 1, pp. 11–19, 1982. View at Google Scholar · View at Scopus
  98. A. K. Ghose and G. M. Crippen, “Modeling the benzodiazepine receptor binding site by the general three-dimensional structure-directed quantitative structure-activity relationship method REMOTEDISC,” Molecular Pharmacology, vol. 37, no. 5, pp. 725–734, 1990. View at Google Scholar · View at Scopus
  99. P. W. Codding and A. K. S. Muir, “Molecular structure of Ro15-1788 and a model for the binding of benzodiazepine receptor ligands. Structural identification of common features in antagonists,” Molecular Pharmacology, vol. 28, no. 2, pp. 178–184, 1985. View at Google Scholar · View at Scopus
  100. A. K. S. Muir and P. W. Codding, “Structure-activity studies of β-carbolines. 3. Crystal and molecular structures of methyl β-carboline-3-carboxylate,” Canadian Journal of Chemistry, vol. 63, no. 10, pp. 2752–2756, 1985. View at Publisher · View at Google Scholar · View at Scopus
  101. M. G. Codding, A. W. Roszak, M. B. Szkaradzinska, J. M. Cook, and L. J. Aha, Modeling of the Benzodiazepine Receptor Using Structural and Theoretical Characterization of Novel Beta-Carbolines, Elsevier Science, Amsterdam, The Netherlands, 1989.
  102. V. Ferretti, P. Gilli, and P. A. Borea, “Structural features controlling the binding of β-carbolines to the benzodiazepine receptor,” Acta Crystallographica Section B: Structural Science, vol. 60, no. 4, pp. 481–489, 2004. View at Publisher · View at Google Scholar · View at Scopus
  103. P. A. Borea, G. Gilli, V. Bertolasi, and V. Ferretti, “Stereochemical features controlling binding and intrinsic activity properties of benzodiazepine-receptor ligands,” Molecular Pharmacology, vol. 31, no. 4, pp. 334–344, 1987. View at Google Scholar · View at Scopus
  104. V. Bertolasi, V. Feretti, G. Gilli, and P. A. Borea, “Stereochemistry of benzodiazepine-receptor ligands.1. Structure of methyl beta-carboline-3-carboxylate (beta-CCM), C13H10N2O2,” Acta Crystallographica Section C: Crystal Structure Communications, vol. 40, p. 1981, 1984. View at Google Scholar
  105. V. Ferretti, V. Bertolasi, G. Gilli, and P. A. Borea, “Structures of two 2-arylpyrazolo[4,3-c]quinolin-3-ones: CGS8216, C16H11N3O, and CGS9896, C16H10ClN3O,” Acta Crystallographica Section C: Crystal Structure Communications, vol. 41, no. 1, pp. 107–110, 1985. View at Publisher · View at Google Scholar
  106. S. Tebib, J.-J. Bourguignon, and C.-G. Wermuth, “The active analog approach applied to the pharmacophore identification of benzodiazepine receptor ligands,” Journal of Computer-Aided Molecular Design, vol. 1, no. 2, pp. 153–170, 1987. View at Publisher · View at Google Scholar · View at Scopus
  107. C. R. Gardner, “A review of recently-developed ligands for neuronal benzodiazepine receptors and their pharmacological activities,” Progress in Neuropsychopharmacology and Biological Psychiatry, vol. 16, no. 6, pp. 755–781, 1992. View at Publisher · View at Google Scholar · View at Scopus
  108. M. S. Allen, A. J. LaLoggia, L. J. Dorn et al., “Predictive binding of β-carboline inverse agonists and antagonists via the CoMFA/GOLPE approach,” Journal of Medicinal Chemistry, vol. 35, no. 22, pp. 4001–4010, 1992. View at Publisher · View at Google Scholar · View at Scopus
  109. Q. Huang, E. Cox, T. Gan et al., “Studies of molecular pharmacophore/receptor models for GABAA/benzodiazepine receptor subtypes: binding affinities of substituted β-carbolines at recombinant alpha x beta 3 gamma 2 subtypes and quantitative structure-activity relationship studies via a comparative molecular field analysis,” Drug Design and Discovery, vol. 16, no. 1, pp. 55–76, 1999. View at Google Scholar
  110. X. He, Q. Huang, C. Ma, S. Yu, R. McKernan, and J. M. Cook, “Pharmacophore/receptor models for GABA(A)/BzR α2β3γ2, α3β3γ2 and α4β3γ2 recombinant subtypes. Included volume analysis and comparison to α1β3γ2, α5β3γ2 and α6β3γ2 subtypes,” Drug Design and Discovery, vol. 17, no. 2, pp. 131–171, 2000. View at Google Scholar · View at Scopus
  111. E. D. Cox, H. Diaz-Arauzo, Q. Huang et al., “Synthesis and evaluation of analogues of the partial agonist 6- (propyloxy)-4-(methoxymethyl)-β-carboline-3-carboxylic acid ethyl ester (6- PBC) and the full agonist 6-(benzyloxy)-4-(methoxymethyl)-β-carboline-3-carboxylic acid ethyl ester (Zk 93423) at wild type and recombinant GABA(A) receptors,” Journal of Medicinal Chemistry, vol. 41, no. 14, pp. 2537–2552, 1998. View at Publisher · View at Google Scholar · View at Scopus
  112. M. J. Martin, M. L. Trudell, H. D. Araúzo et al., “Molecular yardsticks—rigid probes to define the spatial dimensions of the benzodiazepine receptor binding site,” Journal of Medicinal Chemistry, vol. 35, no. 22, pp. 4105–4117, 1992. View at Publisher · View at Google Scholar · View at Scopus
  113. K. Naryanan and J. M. Cook, “Probing the dimensions of the benzodiazepine receptor inverse agonist site,” Heterocycles, vol. 31, no. 2, pp. 203–209, 1990. View at Publisher · View at Google Scholar
  114. S. P. Hollinshead, M. L. Trudell, P. Skolnick, and J. M. Cook, “Structural requirements for agonist actions at the benzodiazepine receptor: studies with analogues of 6-(benzyloxy)-4-(methoxymethyl)-beta-carboline-3-carboxylic acid ethyl ester,” Journal of Medicinal Chemistry, vol. 33, no. 3, pp. 1062–1069, 1990. View at Publisher · View at Google Scholar · View at Scopus
  115. J. M. Cook, H. Diaz-Arauzo, and M. S. Allen, “Inverse agonists: probes to study the structure, topology and function of the benzodiazepine receptor,” in Proceedings of the 51st Annual Scientific Meeting, L. S. Harris, Ed., National Institute on Drug Abuse Research Monograph, pp. 133–139, The College on Problems of Drug Dependence, 1991.
  116. R. Trullas, H. Ginter, B. Jackson et al., “3-Ethoxy-beta-carboline: a high affinity benzodiazepine receptor ligand with partial inverse agonist properties,” Life Sciences, vol. 43, no. 15, pp. 1189–1197, 1988. View at Publisher · View at Google Scholar · View at Scopus
  117. M. Cain, R. W. Weber, F. Guzman et al., “β-Carbolines: synthesis and neurochemical and pharmacological actions on brain benzodiazepine receptors,” Journal of Medicinal Chemistry, vol. 25, no. 9, pp. 1081–1091, 1982. View at Publisher · View at Google Scholar · View at Scopus
  118. X. H. He, C. C. Zhang, and J. M. Cook, “Model of the BzR binding site: correlation of data from site-directed mutagenesis and the pharmacophore/receptor model,” Medicinal Chemistry Research, vol. 10, no. 5, pp. 269–308, 2001. View at Google Scholar · View at Scopus
  119. Q. Huang, R. Y. Liu, P. W. Zhang et al., “Predictive models for GABAA/benzodiazepine receptor subtypes: studies of quantitative structure-activity relationships for imidazobenzodiazepines at five recombinant GABAA/benzodiazepine receptor subtypes [αxβ3γ2 (x = 1−3, 5, and 6)] via comparative molecular field analysis,” Journal of Medicinal Chemistry, vol. 41, no. 21, pp. 4130–4142, 1998. View at Publisher · View at Google Scholar
  120. R. Y. Liu, P. W. Zhang, T. Gan, R. M. McKernan, and J. M. Cook, “Evidence for the conservation of conformational topography at five major GABA(A)/benzodiazepine receptor subsites. Potent affinities of the (S)-enantiomers of framework-constrained 4,5-substituted pyrroloimidazo-benzodiazepines,” Medicinal Chemistry Research, vol. 7, no. 1, pp. 25–35, 1997. View at Google Scholar
  121. Q. Huang, W. Zhang, R. Liu, R. M. McKernan, and J. M. Cook, “Benzo-fused benzodiazepines employed as topological probes for the study of benzodiazepine receptor subtypes,” Medicinal Chemistry Research, vol. 6, no. 6, pp. 384–391, 1996. View at Google Scholar · View at Scopus
  122. S. Yu, X. H. He, C. R. Ma, R. McKernan, and J. M. Cook, “Studies in search of α2 selective ligands for GABAA/BzR receptor subtypes. Part I. Evidence for the conservation of pharmacophoric descriptors for DS subtypes,” Medicinal Chemistry Research, vol. 9, no. 3, pp. 186–202, 1999. View at Google Scholar · View at Scopus
  123. S. Arbilla, H. Depoortere, P. George, and S. Z. Langer, “Pharmacological profile of the imidazopyridine zolpidem at benzodiazepine receptors and electrocorticogram in rats,” Naunyn-Schmiedeberg's Archives of Pharmacology, vol. 330, no. 3, pp. 248–251, 1985. View at Publisher · View at Google Scholar · View at Scopus
  124. G. Wong, K. F. Koehler, P. Skolnick et al., “Synthetic and computer-assisted analysis of the structural requirements for selective, high-affinity ligand binding to diazepam-insensitive benzodiazepine receptors,” Journal of Medicinal Chemistry, vol. 36, no. 13, pp. 1820–1830, 1993. View at Publisher · View at Google Scholar · View at Scopus
  125. A. Camerman and N. Camerman, “Stereochemical basis of anticonvulsant drug action. 2. Molecular structure of diazepam,” Journal of the American Chemical Society, vol. 94, no. 1, pp. 268–272, 1972. View at Publisher · View at Google Scholar · View at Scopus
  126. A. Hempel, N. Camerman, and A. Camerman, “Benzodiazepine stereochemistry: crystal structures of the diazepam antagonist Ro 15-1788 and the anomalous benzodiazepine Ro 5-4864,” Canadian Journal of Chemistry, vol. 65, no. 7, pp. 1608–1612, 1987. View at Publisher · View at Google Scholar · View at Scopus
  127. S. Neidle, G. D. Webster, G. B. Jones, and D. E. Thurston, “Structures of two DNA minor-groove binders, based on pyrrolo[2,1-c][1,4]-benzodiazepines,” Acta Crystallographica Section C: Crystal Structure Communications, vol. 47, no. 12, pp. 2678–2680, 1991. View at Publisher · View at Google Scholar · View at Scopus
  128. T. A. Halgren, “Merck molecular force field. V. Extension of MMFF94 using experimental data, additional computational data, and empirical rules,” Journal of Computational Chemistry, vol. 17, no. 5-6, pp. 616–641, 1996. View at Google Scholar · View at Scopus
  129. T. A. Halgren, “Merck molecular force field. III. Molecular geometries and vibrational frequencies for MMFF94,” Journal of Computational Chemistry, vol. 17, no. 5-6, pp. 553–586, 1996. View at Publisher · View at Google Scholar · View at Scopus
  130. T. A. Halgren, “Merck molecular force field. II. MMFF94 van der Waals and electrostatic parameters for intermolecular interactions,” Journal of Computational Chemistry, vol. 17, no. 5-6, pp. 520–552, 1996. View at Publisher · View at Google Scholar · View at Scopus
  131. T. A. Halgren, “Merck molecular force field. I. Basis, form, scope, parameterization, and performance of MMFF94,” Journal of Computational Chemistry, vol. 17, no. 5-6, pp. 490–519, 1996. View at Publisher · View at Google Scholar · View at Scopus
  132. T. A. Halgren and R. B. Nachbar, “Merck molecular force field. IV. Conformational energies and geometries for MMFF94,” Journal of Computational Chemistry, vol. 17, no. 5-6, pp. 587–615, 1996. View at Google Scholar · View at Scopus
  133. H. L. June, S. C. Harvey, K. L. Foster et al., “GABAAreceptors containing α5 subunits in the CA1 and CA3 hippocampal fields regulate ethanol-motivated behaviors: an extended ethanol reward circuitry,” Journal of Neuroscience, vol. 21, no. 6, pp. 2166–2177, 2001. View at Google Scholar · View at Scopus
  134. B. J. Kaminski, M. L. Van Linn, J. M. Cook, W. Yin, and E. M. Weerts, “Effects of the benzodiazepine GABAA α1-preferring ligand, 3-propoxy-β-carboline hydrochloride (3-PBC), on alcohol seeking and self-administration in baboons,” Psychopharmacology, vol. 227, no. 1, pp. 127–136, 2013. View at Publisher · View at Google Scholar · View at Scopus
  135. S. Huang, Synthesis of Optically Active Subtype Selective Benzodiazepine Receptor Ligands, University of Wisconsin, Milwaukee, Wis, USA, 2007.
  136. M. M. Savić, S. Majumder, S. Huang et al., “Novel positive allosteric modulators of GABAA receptors: do subtle differences in activity at α1 plus α5 versus α2 plus α3 subunits account for dissimilarities in behavioral effects in rats?” Progress in Neuro-Psychopharmacology and Biological Psychiatry, vol. 34, no. 2, pp. 376–386, 2010. View at Publisher · View at Google Scholar · View at Scopus
  137. M. Ernst, D. Brauchart, S. Boresch, and W. Sieghart, “Comparative modeling of GABAA receptors: limits, insights, future developments,” Neuroscience, vol. 119, no. 4, pp. 933–943, 2003. View at Publisher · View at Google Scholar · View at Scopus
  138. B. L. Roth, “Ki determinations were generously provided by the National Institute of Mental Health's Psychoactive Drug Screening Program,” Contract # HHSN-271-2013-00017-C (NIMH PDSP), The NIMH PDSP, 2013, https://pdspdb.unc.edu/pdspWeb/. View at Google Scholar
  139. M. S. Choudhary, S. Craigo, and B. L. Roth, “Identification of receptor domains that modify ligand binding to 5-hydroxytryptamine2 and 5-hydroxytryptamine1c serotonin receptors,” Molecular Pharmacology, vol. 42, no. 4, pp. 627–633, 1992. View at Google Scholar · View at Scopus
  140. J. Yang, Y. Teng, S. Ara, S. Rallapalli, and J. M. Cook, “An improved process for the synthesis of 4H-imidazo[1,5-a][1,4]benzo­diazepines,” Synthesis, no. 6, pp. 1036–1040, 2009. View at Publisher · View at Google Scholar · View at Scopus
  141. Z.-Q. Gu, G. Wong, C. Dominguez, B. R. De Costa, K. C. Rice, and P. Skolnick, “Synthesis and evaluation of imidazo[1,5-a][1,4]benzodiazepine esters with high affinities and selectivities at ‘diazepam-insensitive’ benzodiazepine receptors,” Journal of Medicinal Chemistry, vol. 36, no. 8, pp. 1001–1006, 1993. View at Publisher · View at Google Scholar · View at Scopus
  142. J. Buckingham, Dictionary of Organic Compounds, vol. 2, Chapman & Hall, New York, NY, USA, 1982.
  143. C. Yung-Chi and W. H. Prusoff, “Relationship between the inhibition constant (KI) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction,” Biochemical Pharmacology, vol. 22, no. 23, pp. 3099–3108, 1973. View at Publisher · View at Google Scholar · View at Scopus
  144. J. M. Cook, T. Clayton, Y. T. Johnson, S. Rallapalli, and D. Han, “GABAergic agents to treat memory deficits,” US Patent 2010/0130479 A1, 2010.