Pharmaceutisch Weekblad

, Volume 4, Issue 5, pp 145–153 | Cite as

Pharmacodynamic effects and possible therapeutic uses of THIP, a specific GABA-agonist

  • A. V. Christensen
  • O. Svendsen
  • P. Krogsgaard-Larsen
Medicinal Chemistry Congress


thip (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) is a potent and specificgaba receptor agonist which does not influence thegaba uptake system orgaba metabolizing enzymes. The specificity for thegaba receptor is also demonstrated by lack of action on monoaminergic, cholinergic, histaminergic or opiate receptors.

Since in recent yearsgaba receptor stimulants — among othersthip — have become available many have speculated as to what clinical indicationgaba-ergic stimulation might be an important element. The first suggestion was thatgaba-ergic drugs by an inhibitory effect on the dopamine neurons would improve the antischizophrenic effect of neuroleptics and improve tardive dyskinesia. Furthermore, studies on brains of deceased Parkinson and Huntington's chorea patients have demonstrated a low level ofgaba and its synthesizing enzyme glutamic acid decarboxylase (gad) in the basal ganglia. Also in epilepsy and diseases with dementia a deficit in thegaba system has been proposed. Therefore a therapeutic strategy for these diseases may be supplementary treatment with drugs which increasegaba receptor activity.

Furthermore, recent results in humans have shown thatgaba agonists perhaps also could be of benefit in mania and depressions. When considering the neurophysiological elements of nociception and muscle tone it is also reasonable to suggest thatgaba-ergic stimulation may reduce pain perception and muscle tone.


Dopamine Dementia Glutamic Acid Muscle Tone Tardive Dyskinesia 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Antonaccio, M.J., L. Kerwin andD.G. Taylor (1978)Neuropharmacol. 17, 597–603.Google Scholar
  2. Arnt, J., A.V. Christensen andJ. Scheel-Krüger (1979)J. Pharm. Pharmacol, 31, 56–58.Google Scholar
  3. Chase, T.N., N.S. Wexler andA. Barbeau (Eds.) (1979)Huntington's Disease. Raven Press, New York.Google Scholar
  4. Christensen, A.V., andJ. Hyttel (1981)Drug Development Research 1, 255–263.Google Scholar
  5. Christensen, A.V., and J.-J.Larsen (1982)Pol. J. Pharmacol. Pharm., in press.Google Scholar
  6. Christensen, A.V., and O.Svendsen (1982)Brain Res. Bull., suppl., in press.Google Scholar
  7. Christensen, A.V., B. Fjalland andI. Møller Nielsen (1976)Psychopharmacology 48, 1–6.Google Scholar
  8. Christensen, A.V., J. Arnt andJ. Scheel-Krüger (1978)Eur. J. Pharmacol. 48, 459–462;Ibidem (1979)Life Sci. 24, 1395–1402.Google Scholar
  9. Cools, A.R. (1979)Life Sci. 25, 2475–2484.Google Scholar
  10. Costall, B., R.J. Naylor andR.T. Owen (1978)Eur. J. Pharmacol. 49, 402–413.Google Scholar
  11. Curtis, D. R., andG.A.R. Johnston (1974)Ergeb. Physiol. Biol. Exp. Pharmakol. 69, 97.Google Scholar
  12. Curtis, D.R., A.W. Duggan, D. Felix andG.A.R. Johnston (1971)Brain Res. 32, 69.Google Scholar
  13. Delini-Stula, A. (1979) In:Gaba-Neurotransmitters (Krogsgaard-Larsen, P., andH. Kofod, Eds.). Munksgaard, Copenhagen, 482.Google Scholar
  14. Dimicco, J.A., K. Gale, B. Hamilton andR.A. Gillis (1979)Science 204, 1106.Google Scholar
  15. Emrich, H.E. (1981). In:Biological Psychiatry (Perris, C., G. Struwe andB. Jansson, Eds.). Elsevier/North-Holland Biomedical Press, Amsterdam, 433–439.Google Scholar
  16. Falch, E., andP. Krogsgaard-Larsen (1982)J. Neurochem. 38, 1123–1129.Google Scholar
  17. Ferkany, J.W., andS.J. Enna (1980)Life Sci. 27, 143–149.Google Scholar
  18. Fonnum, F. (Ed.) (1978)Amino Acids as Chemical Transmitters. Plenum Press, New York.Google Scholar
  19. Garau, L., S. Govoni, E. Stafanini, M. Trabucchi andP.F. Spano (1978)Life Sci. 23, 1745–1750.Google Scholar
  20. Gerner, R.H., andT.A. Hare (1981)Am. J. Psychiat. 138, (8), 1098–1101.Google Scholar
  21. Gold, B.J., M.B. Bowers, M.D. Robert, H. Roth andD.W. Sweeney (1980)Am. J. Psychiat. 137 (3), 362–364.Google Scholar
  22. Gottfries, C.G. (1980)TINS 3, 55–57.Google Scholar
  23. Grandison, L., andA. Guidotti (1979)Endocrinology 105, 754–759.Google Scholar
  24. Hill, R.C. (1982) Personal communication.Google Scholar
  25. Hill, R.C., R. Maurer, H.H. Buescher andD. Römer (1981)Eur. J. Pharmacol. 69, 221–224.Google Scholar
  26. Hyttel, J. (1978)Life Sci. 23, 551–556;Ibidem (1982) Personal communication.Google Scholar
  27. Johnston, G.A.R., S.M.E. Kennedy andD. Lodge (1978)J. Neurochem. 31, 1519–1523.Google Scholar
  28. Krogsgaard-Larsen, P. (1980)Mol. Cell. Biochem. 31, 105–121.Google Scholar
  29. Krogsgaard-Larsen, P., andG.A.R. Johnston (1978)J. Neurochem. 30, 1377–1382.Google Scholar
  30. Krogsgaard-Larsen, P., andA.V. Christensen (1980)Ann. Rep. Med. Chem. 15, 41–50.Google Scholar
  31. Krogsgaard-Larsen, P., G.A.R. Johnston, D. Lodge andD.R. Curtis (1977)Nature 268, 53–55.Google Scholar
  32. Krogsgaard-Larsen, P., J. Scheel-Krüger andH. Kofod (Eds.) (1979a)GABA-Neurotransmitters. Pharmacochemical, Biochemical and Pharmacological Aspects. Munksgaard, Copenhagen.Google Scholar
  33. Krogsgaard-Larsen, P., H. Hjeds, D.R. Curtis, D. Lodge andG.A.R. Johnston (1979b)J. Neurochem. 32, 1717–1724.Google Scholar
  34. Lambert, P.-A., G. Caraz, S. Borselli andS. Carrel (1966)Ann. Med. Psychol. 1, 707–710.Google Scholar
  35. Lambert, P.-A., S. Borselli, G. Marcou, M. Bouchardy andC. Cabrol (1971)Ann. Med. Psychol. 2, 442–447.Google Scholar
  36. Lambert, P.-A., G. Carraz, S. Borselli andM. Bouchardy (1975)l'Encephale 1, 25–31.Google Scholar
  37. Lloyd, K.G., L. Shemen andO. Hornykiewicz (1977)Brain Res. 127, 269–278.Google Scholar
  38. Lloyd, K.G., C. Munari, L. Bossi, J. Bancaud, J. Talairach andP.L. Morselli (1981) In:Neurotransmitters, Seizures and Epilepsy (Morselli, P.L., E.H. Reynolds, K.G. Lloyd, W. Löscher andB.S. Beldrum, Eds.). Raven Press, New York, 325–338.Google Scholar
  39. Locatelli, V., D. Cocchi, C. Frigerio, R. Betti, P. Krogs-Gaard-Larsen, G. Racagni andE. Müller (1979)Endocrinology 105, 778–785.Google Scholar
  40. Möhler, H., andT. Okada (1977)Nature 267, 65–67;Ibidem (1978)Mol. Pharmacol. 14, 256–265.Google Scholar
  41. Naik, S.R., A. Guidotti andE. Costa (1976)Neuropharmacol. 15, 479–484.Google Scholar
  42. Neal, M.J., andN.G. Bowery (1977)Brain Res. 138, 169.Google Scholar
  43. Oberlander, C., D. Dumont andJ.R. Boissier (1977).Eur. J. Pharmacol. 43, 389–390.Google Scholar
  44. Olianas, M.C., G.M. De Montis, G. Mulas andA. Tagliamonte (1978)Eur. J. Pharmacol. 49, 233–241.Google Scholar
  45. Olpe, H.R., H. Schellenbeg andW.P. Koella (1977)Eur. J. Pharmacol. 45, 291–294.Google Scholar
  46. Olsen, R.W., M.O. Bergman, P.C. Van Ness, S.C. Lummis, A.E. Watkins, C. Napias andD.V. Greenlee (1981)Mol. Pharmacol. 19, 217–227.Google Scholar
  47. Palfreyman, M.G., P.J. Schechter, W.R. Buckett, G.P. Tell andJ. Koch-Weser (1981)Biochem. Pharmacol. 30, 817.Google Scholar
  48. Pedersen, V., andA.V. Christensen (1972)Acta Pharmacol. Toxicol. 31, 488–496.Google Scholar
  49. Perry, E.K. (1980)Age and Ageing 9, 1–8.Google Scholar
  50. Perry, T.L., J. Buchanan, S.J. Kish andS. Hansen (1979)Lancet I, 237–239.Google Scholar
  51. Pradhan, S.N. (1980)Life Sci. 26, 1643–1656.Google Scholar
  52. Randrup, A., I. Munkvad, R. Fog, J. Gerlach, L. Molander, B. Kjellberg andJ. Scheel-Krüger (1975) In:Current Development in Psychopharmacology, 2 (Essman, W.B. andL. Valzelli, Eds.). Spectrum, New York, 207–248.Google Scholar
  53. Ribak, C.E., A.B. Harris, J.E. Vaughn andE. Roberts (1979)Science 205, 211–214.Google Scholar
  54. Roberts, E., T.N. Chase andD.B. Tower (Eds.) (1976)GABA in Nervous System Function. Raven Press, New York.Google Scholar
  55. Scheel-Krüger, J., andA.V. Christensen (1980) In:Long Term Effects of Neuroleptics (Costa, E.,et al., Eds.). Raven Press, New York.Google Scholar
  56. Scheel-Krüger, J., J. Arnt andG. Magelund (1977)Neurosci. Lett. 4, 351–356.Google Scholar
  57. Scheel-Krüger, J., A.V. Christensen andJ. Arnt (1978)Life Sci. 22, 75–84.Google Scholar
  58. Scheel-Krüger, J., J. Arnt, C. Bræstrup, A.V. Christensen andG. Magelund (1979) In:GABA-Neurotransmitters (Krogsgaard-Larsen, P., J. Scheel-Krüger andH. Kofod, Eds.). Munksgaard, Copenhagen, 447–466.Google Scholar
  59. Schwarcz, R., I. Creese, J.I. Coyle andS. Snyder (1978)Nature 271, 766–768.Google Scholar
  60. Spokes, E.G.S., N.J. Garrett, M.N. Rossor andL.L. Iversen (1980)J. Neurol. Sci. 48, 303.Google Scholar
  61. Schousboe, A., P. Thorbek, L. Hertz andP. Krogsgaard-Larsen (1979)J. Neurochem. 33, 181–189.Google Scholar
  62. Waddington, J.L. (1977)Brit. J. Pharmacol. 60, 263–264.Google Scholar
  63. Zimmermann, M. (1979) In:Advances in Pain Research and Therapy (Bonica, J.J., Ed.). Raven Press, 3, 3–32.Google Scholar

Copyright information

© Royal Dutch Association for Advancement of Pharmacy 1982

Authors and Affiliations

  • A. V. Christensen
    • 1
  • O. Svendsen
    • 1
  • P. Krogsgaard-Larsen
    • 2
  1. 1.Department of Pharmacology and ToxicologyH. Lundbeck & Co. A/SValbyDenmark
  2. 2.Department of Chemistry BCRoyal Danish School of PharmacyCopenhagen Ø.Denmark

Personalised recommendations