Benzodiazepine Receptor Ligands with Positive and Negative Efficacy

  • Claus Braestrup
  • Mogens Nielsen
  • Tage Honoré
Part of the NATO ASI Series book series (NSSA, volume 72)


A major advance in the understanding of the mechanism of action of benzodiazepines and in the understanding of anxiety was the discovery, in 1977, of benzodiazepine (BZ) receptors1, 2 (for a review3). Radioactively labelled diazepam binds to a protein in the neuronal plasma membrane and this membrane protein was shown to be embedded in the outer lipid membrane of the cell. Studies with the selective neurotoxic agent kainic acid and on the mutant “nervous” mouse (nr/nr) (in which the Purkinje cells in the cerebellum completely degenerate) located the binding protein to neurons in the central nervous system. High affinity BZ receptors are not found peripherally.


Gaba Receptor Inverse Agonist Gaba Agonist Photoaffinity Labelling Pharmacological Efficacy 
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  1. 1.
    R.F. Squires and C. Braestrup, Benzodiazepine receptors in rat brain, Nature 266: 732 (1977).PubMedCrossRefGoogle Scholar
  2. 2.
    H. Moehler and T. Okada, Properties of 3H-diazepam binding to benzodiazepine receptors in rat cerebral cortex, Life Sci. 20: 2101 (1977).CrossRefGoogle Scholar
  3. 3.
    C. Braestrup and M. Nielsen, Benzodiazepine receptors, in: Handbook of Psychopharmacology, vol. 17, L.L. Iversen, S.D. Iversen, and S.H. Snyder, eds. pp. 285–384. Plenum Press, New York (1982).Google Scholar
  4. 4.
    C. Braestrup, R. Schmiechen, M. Nielsen, and E.N. Petersen, Benzodiazepine ligands, receptor occupancy, pharmacological effect and GABA receptor coupling, in: Pharmacology of Benzodiazepines, S.M. Paul et al., eds. McMillan Press (in press).Google Scholar
  5. 5.
    R.F. Squires, D.I. Benson, C. Braestrup, J. Coupet, C.A. Klepner, V. Myers, and B. Beer, Some properties of brain specific benzodiazepine receptors: New evidence for multiple receptors. Pharmacol. Biochem. Behay. 10: 825 (1979).CrossRefGoogle Scholar
  6. 6.
    C. Braestrup and M. Nielsen, Multiple benzodiazepine receptors, Trends Neurosci. 3: 301 (1980).Google Scholar
  7. 7.
    W. Sieghart and M. Karobath, Molecular heterogeneity of benzodiazepine receptors, Nature (London) 286: 285 (1980).CrossRefGoogle Scholar
  8. 8.
    W.S. Young, M.J. Kuhar, Autoradiog~` grap c localization of benzodiazepine receptor in the brains of humans and animals. Nature 280: 393 (1979).CrossRefGoogle Scholar
  9. 9.
    C. Braestrup, R. Schmiechen, G. Neff, M. Nielsen, and E.N. Petersen, Interaction of convulsive ligands with benzodiazepine receptors, Science 216: 1241 (1982).PubMedCrossRefGoogle Scholar
  10. 10.
    J.F. Tallman, J.W. Thomas, and D.W. Gallager, GABAergicGoogle Scholar
  11. 11.
    modulation of benzodiazepine binding site sensitivity, Nature 274: 383 (1978).CrossRefGoogle Scholar
  12. 12.
    M. Nielsen, H. Schou, and C. Braestrup, 3H-Propyl ß-carboline-3-carboxylate binds specifically to brain benzodiazepine receptors, J. Neurochem. 36: 276 (1981).PubMedCrossRefGoogle Scholar
  13. 13.
    J. Patel, P. Marangos, and F. Goodwin, [3H1Ethyl-ß-carboline3-carboxylate binding to the benzodiazepine receptor is not affected by GABA, Eur. J. Pharmacol. 72: 419 (1981).PubMedCrossRefGoogle Scholar
  14. 14.
    H. Möhler and J.G. Richards, Agonist and antagonist benzodiazepine receptor interaction in vitro, Nature 294: 763 (1981).PubMedCrossRefGoogle Scholar
  15. 15.
    A.J. Czernik, B. Petrack, H.J. Kalinsky, S. Psychoyos, W.D. Cash, C. Tsai, R.K. Rinehart, F.R. Granat, R.A. Lovell, D.E. Brundish, and R. Wade, CGS 8216: Receptor binding characteristics of a potent benzodiazepine antagonist. Life Sci. 30: 363 (1982).PubMedCrossRefGoogle Scholar
  16. 16.
    F.J. Ehlert, W.R. Roeske, C. Braestrup, S.H. Yamamura, and H.I. Yamamura, y-Aminobutyric acid regulation of the benzodiazepine receptor: Biochemical evidence for pharmacologically different effects of benzodiazepines and propyl ß-carboline-3-carboxylate, Eur. J. Pharmacol. 70: 593 (1981).PubMedCrossRefGoogle Scholar
  17. 17.
    M. Fujimoto, K. Hirai, and T. Okabayashi, Comparison of the effects of GABA and chloride ion on the affinities of ligands for the benzodiazepine receptor, Life Sci. 30: 51 (1982).PubMedCrossRefGoogle Scholar
  18. 18.
    A. Doble, I.L. Martin, and D.A. Richards, GABA modulation predicts biological activity of ligands for the benzodiazepine receptor, Brit. J. Pharmacol. 76: 238P (1982).Google Scholar
  19. 19.
    P. Skolnick, M.M. Schwweri, Ë.F. Williams, V.Y. Moncada, and S.M. Paul, An in vitro binding assay which differentiates benzodiazepine “agonists” and “antagonists”, Eur. J. Pharmacol. 78: 133 (1982).PubMedCrossRefGoogle Scholar
  20. 20.
    J.H. Skerritt, L.P. Davies, S. Chen Chow, and G.A.R. Johnston, Contrasting regulation by GABA of the displacement of benzodiazepine antagonist binding by benzodiazepine agonists and purines, Neurosci. Lett. 32: 169 (1982).Google Scholar
  21. 21.
    C. Braestrup and M. Nielsen, GABA reduces binding of 3H-methyl 13-carboline-3-carboxylate to brain benzodiazepine receptors. Nature 294: 472 (1981).PubMedCrossRefGoogle Scholar
  22. 22.
    B.J. Jones and N.R. Oakley, The convulsant properties of methyl 13-carboline-3-carboxylate in the mouse. Brit. J. Pharmacol. 74: 884P (1981).Google Scholar
  23. 23.
    M. Schweri, M. Cain, J. Cook, S. Paul, and P. Skolnick, Blockade of 3-carbomethoxy-ß-carboline induced seizures by diazepam and the benzodiazepine antagonists, Ro 15–1788 and CGS 8216, Pharmacol. Biochem. Behay. 17: 457 (1982).CrossRefGoogle Scholar
  24. 24.
    A. Valin, R.H. Dodd, D.R. Liston, P. Po’t ‘r, and J. Rossier, Methyl-ß-carboline-induced convulsions are antagonized by Ro 15–1788 and by propyl-ß-carboline, Eur. J. Pharmacol. 85: 93 (1982).PubMedCrossRefGoogle Scholar
  25. 25.
    C. Braestrup, M. Nielsen, and T. Honoré, Binding of [3H]-DMCM, a convulsive benzodiazepine ligand, to rat brain membranes. Preliminary studies. J. Neurochem. (1982) (submitted).Google Scholar
  26. 26.
    L.R. Chang, E.A. Barnard, M.M.S. Lo, and J.O. Dolly, Molecular sizes of benzodiazepine receptors and the interacting GABA receptors in the membrane are identical, FEBS Lett. 126: 309 (1981).PubMedCrossRefGoogle Scholar
  27. 27.
    M. Nielsen, T. Honoré, and C. Braestrup, Enhanced binding of the convulsive ligand, DMCM, to high-energy irradiated benzodiazepine receptors; evidence of complex receptor structure, Biochem. Pharmacol. (1982) (in press).Google Scholar
  28. 28.
    M. Karobath and P. Supavilai, Distinction of benzodiazepine agonists from antagonists by photoaffinity labelling of benzodiazepine receptors in vitro, Neurosci. Lett. 31: 65 (1982).Google Scholar
  29. 29.
    R. Dorow, ß-carboline monomethylamide causes anxiety in man. 13th Collegium Internationale Neuro-psychopharmacologicum Congress (Jerusalem, June 20–25, 1982 ): Abstr. I.Google Scholar
  30. 30.
    H. Mahler, Benzodiazepine receptors: Differential interaction of benzodiazepine agonists and antagonists after photo-affinity labelling with flunitrazepam. Eur. J. Pharmacol. 80: 435 (1982).CrossRefGoogle Scholar
  31. 31.
    R.W. Gee and H.I. Yamamura, Differentiation of [3H] benzodiazepine antagonist binding following the photolabelling of benzodiazepine receptors. Eur. J. Pharmacol. 82: 239 (1982).PubMedCrossRefGoogle Scholar
  32. 32.
    C.L. Brown and I.L. Martin, Photoaffinity labelling of the benzodiazepine receptor does not occlude the ßCCE binding site, Brit. J. Pharmacol. 77: 312P (1982).Google Scholar
  33. 33.
    J.W. Thomas and J.F. Tallman, Conversion of high-affinity benzodiazepine binding sites to low-affinity by photo-labelling, Soc. Neurosci. 402 (1982) (Abstract).Google Scholar
  34. 34.
    T. Costa, D. Rodbard, and C.B. Pert, Is the benzodiazepine receptor coupled to a chloride anion channel? Nature (London), 277: 315 (1979).CrossRefGoogle Scholar
  35. 35.
    I.L. Martin and J.M. Candy, Facilitation of specific benzodiazepine binding in rat brain membrane fragments by a number of anions, Neuropharmacology 19: 175 (1980).PubMedCrossRefGoogle Scholar
  36. 36.
    R.W. Olsen, Drug interactions at the GABA receptor-ionophore complex, Ann. Rev. Pharmacol. Toxicol. 22: 245 (1982).CrossRefGoogle Scholar
  37. 37.
    W. Haefely, P. Polc, R. Schaffner, H.H. Keller, L. Pieri, and H. Moehler, Facilitation of GABAergic transmission by drugs, in: “Gaba-Neurotransmitters”, P. Krogsgaard-Larsen, J. Scheel-Krueger, and H. Kofod, eds., pp. 357–375, Munksgaard, Copenhagen and Academic Press, New York (1979).Google Scholar
  38. 38.
    C. Braestrup and M. Nielsen, Anxiety, Lancet 11: 1030 (1982).CrossRefGoogle Scholar
  39. 39.
    T. Heidmann and J-P. Changeux, Fast kine— tic studies on the allosteric interactions betweenn acetylcholine receptor and local anesthetic binding sites, Eur. J. Biochem. 94: 281 (1979).PubMedCrossRefGoogle Scholar
  40. 40.
    W.C. Bowman and M.J. Rand, Textbook of Pharmacology, 2nd edition, Blackwell Scientific Publications, Oxford (1980).Google Scholar
  41. 41.
    R.E. Study and J.Z. Barker, Diazepam and (-)-pentobarbital: Fluctuation analysis reveals different mechanisms for potentiation of y-aminobutyric acid responses in cultured central neurons, Proc. Natl. Acad. Sci. 78: 7180 (1981).PubMedCrossRefGoogle Scholar
  42. 42.
    R.A. O’Brien, W. Schlosser, N.M. Spirt, S. Franco, W.D. Horst, P. Polc, and E.P. Bonetti, Antagonism of benzodiazepine receptors by beta carbolines, Life Sci. 29: 75 (1981).PubMedCrossRefGoogle Scholar
  43. 43.
    D.W. Choi, D.H. Farb, and G.D. Fischbach, Chlordiazepoxide selectively augments GABA action in spinal cord cell cultures. Nature (London) 269: 342 (1977).CrossRefGoogle Scholar
  44. 44.
    C.Y. Chan, T.T. Gibbs, and D.H. Farb, Action of beta-carboline in flunitrazepam-photolinked cultures, Soc. Neurosci. 572 (1982) (Abstract).Google Scholar
  45. 45.
    M. Skovgaard Jensen and J.D.C. Lambert, The interaction of DMCM (a ß-carboline derivative) with inhibitory amino acid responses on cultured mouse neurones (submitted).Google Scholar
  46. 46.
    A. Guidotti, G. Toffano, and E. Costa, An endogenous protein modulates the affinity of GABA and benzodiazepine receptors in rat brain, Nature 275: 553 (1978).PubMedCrossRefGoogle Scholar
  47. 47.
    J.H. Skerritt, M. W-illow, and G.A.R. Johnston, Diazepam enhancement of low affinity GABA binding to rat brain membranes, Neurosci. Lett. 29: 63 (1982).Google Scholar
  48. 48.
    B.A. Meiners and A.I. Salama, A criterion for distinguishing benzodiazepines from their antagonists, Soc. Neurosci. 402 (1982) (Abstract).Google Scholar
  49. 49.
    J.H. Skerritt, G.A.R. Johnston, and C. Braestrup, Modulation of GABA binding to rat brain membranes by alkyl ß-carboline-3-carboxylate esters, Eur. J. Pharmacol. (1982) (in press).Google Scholar
  50. 50.
    D.J. Nutt and P.J. Cowen, Unusual interactions of benzodiazepine receptor antagonists, Nature 295: 436 (1982).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1984

Authors and Affiliations

  • Claus Braestrup
    • 1
    • 2
  • Mogens Nielsen
    • 1
  • Tage Honoré
    • 2
  1. 1.Sct. Hans Mental HospitalRoskildeDenmark
  2. 2.A/S FerrosanSoeborgDenmark

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