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Chemical Compound Review

T101_ALDRICH     7-oxa-4,8- diazabicyclo[4.3.0]non-10-en- 9...

Synonyms: THIP NIEaNI, AC1NWAX4, SureCN567226, T101_SIGMA, AG-G-42489, ...
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Disease relevance of gaboxadol


Psychiatry related information on gaboxadol


High impact information on gaboxadol

  • THIP, a hypnotic and antinociceptive drug, enhances an extrasynaptic GABAA receptor-mediated conductance in mouse neocortex [10].
  • Since its cellular actions in the neocortex are uncertain, we studied the effects of THIP on neurons in slices of frontoparietal neocortex of 13- to 19-day-old (P13-19) mice [10].
  • Binding was displaced in a dose-related manner by the GABA agonists muscimol (KI = 1 X 10(-8) M), isoguvacine (KI = 6 X 10(-7) M), THIP (4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridin-3-ol); KI = 5 X 10(-6) M), and the antagonist (+)bicuculline (KI = 5 X 10(-5) M) but not its inactive stereoisomer (-)bicuculline (KI greater than 10(-3) M) [11].
  • THIP treatment of 7-day-old cultures led to a statistically significant increase in the cytoplasmic density of rough endoplasmic reticulum, Golgi apparatus, vesicles, and coated vesicles, whereas no significant increase in the cytoplasmic density of these organelles was observed in 14-day-old cultures exposed to THIP for 6 h [12].
  • The decrease in GLDH specific activity observed in THIP-treated rats during their late postnatal development possibly indicates a repression of glutamatergic neurons [13].

Chemical compound and disease context of gaboxadol


Biological context of gaboxadol


Anatomical context of gaboxadol

  • Our studies suggest that THIP activates an extrasynaptic GABA(A) receptor-mediated conductance in the neocortex, which may alter the cortical network activity [10].
  • The binding of radioactive THIP to thoroughly washed, frozen, and thawed membranes isolated from rat brains has been studied at 2 degrees C under sodium ion-free conditions and compared with the binding of [3H]GABA and [3H]piperidine-4-sulphonic acid ([3H]P4S) [20].
  • Depolarization-induced release of [3H]gamma-aminobutyric acid ([3H]-GABA) from preloaded slices of rat cerebral cortex was inhibited by muscimol and THIP in a dose-dependent fashion [21].
  • A series of compounds structurally related to 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP), which previously were shown to antagonize glycine responses in cat spinal cord, inhibited [3H]strychnine binding in micromolar concentrations [22].
  • Examination by light microscopy demonstrated that the major effect of THIP was to increase alpha6 subunit clustering on granule cell bodies as well as neurites, 15-fold and sixfold, respectively [23].

Associations of gaboxadol with other chemical compounds

  • 5-(4-Piperidyl)isoxazol-3-ol (4-PIOL, 10), a structural analog of 4-aminobutanoic acid (GABA, 1) and the GABAA agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP, 5), is a low-efficacy partial GABAA agonist [24].
  • The data provide evidence for a functional supersensitivity of GABA-sensitive nondopaminergic projections from the substantia nigra in response to chronic neuroleptic treatment and reveal differences between the precise sites or modes of action of baclofen, muscimol, and THIP within this structure [25].
  • However, in the presence and absence of bicuculline, THIP reduced the total number of benzodiazepine binding sites, probably in a bicuculline insensitive manner [26].
  • Naloxone, 4,5,6,7-tetrahydroisoxazolo(S,4-C)pyridin-3-ol (THIP) hydrate and haloperidol inhibited binding poorly (Ki greater than 1 microM), suggesting that these compounds do not interact significantly with the high affinity PCP receptor in vivo [27].
  • GABA (10 micrograms) and two other GABA agonists [4,5,6,7-tetrahydroisoxazolo[5, 40c]pyridin-3-ol (THIP), 300 ng and chlordiazepoxide, 10-30 micrograms], microinjected into the inferior colliculus, also reduced audiogenic seizure susceptibility [28].

Gene context of gaboxadol

  • Paradoxical blockade of a muscimol response by THIP, a GABA agonist and also by GABA-transaminase inhibitors [29].
  • THIP has been reported to increase EEG slow-wave activity (SWA; EEG power in the 0.75-4 Hz band) in non-REM (NREM) sleep in both rats and humans [30].
  • Although THP withdrawal in delta knockout mice also increased the alpha4 GABAR subunit, the anxiogenic effects of THP and the anxiolytic effects of THIP were not observed, implicating alpha4betadelta GABAR in these effects [31].
  • Hence, the ability of THIP to induce low-affinity GABAA receptors was prevented by the simultaneous depletion of the cellular content of putrescine and spermidine, whereas inhibition of ornithine decarboxylase and of putrescine formation was not sufficient to prevent THIP-induced receptor formation [32].
  • THIP is thus not effective against reflex epilepsy [3].

Analytical, diagnostic and therapeutic context of gaboxadol

  • The effect of 4,5,6,7-tetrahydroisoxazolo[5,4-c]-pyridin-3-ol (THIP) on the ultrastructural composition of cultured cerebellar granule cells was investigated during development by quantitative electron microscopy (morphometric analysis) [12].
  • The closely related 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP, 3), although biologically less active than muscimol, was selected for clinical trials [33].
  • The two higher doses of THIP induced an abnormal EEG pattern both in waking and NREM sleep [30].
  • THIP induced analgesia as well as sedation and loss of righting reflex [34].
  • Using in situ hybridization, a small THIP-induced increase in alpha6 mRNA was detected at 4 DIV; however, no effect was apparent at 8 DIV [23].


  1. Central cardiovascular effects produced by the GABA receptor agonist drug, THIP. Gillis, R.A., Williford, D.J., Dias Souza, J., Quest, J.A. Neuropharmacology (1982) [Pubmed]
  2. Methylphenidate, apomorphine, THIP, and diazepam in monkeys: dopamine-GABA behavior related to psychoses and tardive dyskinesia. Gerlach, J., Bjørndal, N., Christensson, E. Psychopharmacology (Berl.) (1984) [Pubmed]
  3. Effects of the bicyclic GABA agonist, THIP, on myoclonic and seizure responses in mice and baboons with reflex epilepsy. Meldrum, B., Horton, R. Eur. J. Pharmacol. (1980) [Pubmed]
  4. GABAergic modulation of nociceptive threshold: effects of THIP and bicuculline microinjected in the ventral medulla of the rat. Drower, E.J., Hammond, D.L. Brain Res. (1988) [Pubmed]
  5. THIP treatment of Huntington's disease. Foster, N.L., Chase, T.N., Denaro, A., Hare, T.A., Tamminga, C.A. Neurology (1983) [Pubmed]
  6. The GABAA agonist THIP produces slow wave sleep and reduces spindling activity in NREM sleep in humans. Faulhaber, J., Steiger, A., Lancel, M. Psychopharmacology (Berl.) (1997) [Pubmed]
  7. THIP inhibits feeding behavior in fasted rats. Blavet, N., De Feudis, F.V., Clostre, F. Psychopharmacology (Berl.) (1982) [Pubmed]
  8. GABAergic drugs and sexual motivation, receptivity and exploratory behaviors in the female rat. Agmo, A., Soria, P. Psychopharmacology (Berl.) (1997) [Pubmed]
  9. Effects of THIP on chronic anxiety. Hoehn-Saric, R. Psychopharmacology (Berl.) (1983) [Pubmed]
  10. THIP, a hypnotic and antinociceptive drug, enhances an extrasynaptic GABAA receptor-mediated conductance in mouse neocortex. Drasbek, K.R., Jensen, K. Cereb. Cortex (2006) [Pubmed]
  11. gamma-Aminobutyric acid- and benzodiazepine-binding sites in human anterior pituitary tissue. Grandison, L., Cavagnini, F., Schmid, R., Invitti, S.C., Guidotti, A. J. Clin. Endocrinol. Metab. (1982) [Pubmed]
  12. Gamma-aminobutyric acid agonist-induced alterations in the ultrastructure of cultured cerebellar granule cells is restricted to early development. Hansen, G.H., Belhage, B., Schousboe, A., Meier, E. J. Neurochem. (1988) [Pubmed]
  13. Effect of repeated treatment with a gamma-aminobutyric acid receptor agonist on postnatal neural development in rats. Meier, E., Jørgensen, O.S., Schousboe, A. J. Neurochem. (1987) [Pubmed]
  14. GABAergic drugs and lordosis behavior in the female rat. Agmo, A., Soria, P., Paredes, R. Hormones and behavior. (1989) [Pubmed]
  15. Pharmacological analysis of the central cardiovascular effects of four GABA analogues. Bousquet, P., Feldman, J., Bloch, R., Schwartz, J. Naunyn Schmiedebergs Arch. Pharmacol. (1984) [Pubmed]
  16. Clinical activity of GABA agonists in neuroleptic- and L-dopa-induced dyskinesia. Morselli, P.L., Fournier, V., Bossi, L., Musch, B. Psychopharmacology. Supplementum. (1985) [Pubmed]
  17. Anticonvulsant action of GABA agonists and prodrugs on minor and major seizures in epileptic gerbils. Comparison with mouse models of seizure states. Löscher, W. Archives internationales de pharmacodynamie et de thérapie. (1985) [Pubmed]
  18. omega-Conotoxin binding sites and regulation of transmitter release in cerebellar granule neurons. Elster, L., Saederup, E., Schousboe, A., Squires, R.F. J. Neurosci. Res. (1994) [Pubmed]
  19. Effects of unilateral microinjections of GABAergic drugs into the inferior colliculus on auditory evoked potentials and on audiogenic seizure susceptibility. Bagri, A., Sandner, G., Di Scala, G. Exp. Neurol. (1989) [Pubmed]
  20. The binding of the GABA agonist [3H]THIP to rat brain synaptic membranes. Falch, E., Krogsgaard-Larsen, P. J. Neurochem. (1982) [Pubmed]
  21. GABA autoreceptors are not coupled to benzodiazepine receptors in rat cerebral cortex. Brennan, M.J. J. Neurochem. (1982) [Pubmed]
  22. Glycine antagonists structurally related to 4,5,6,7-tetrahydroisoxazolo [5,4-c]pyridin-3-ol inhibit binding of [3H]strychnine to rat brain membranes. Braestrup, C., Nielsen, M., Krogsgaard-Larsen, P. J. Neurochem. (1986) [Pubmed]
  23. Expression of the GABA(A) receptor alpha6 subunit in cultured cerebellar granule cells is developmentally regulated by activation of GABA(A) receptors. Carlson, B.X., Belhage, B., Hansen, G.H., Elster, L., Olsen, R.W., Schousboe, A. J. Neurosci. Res. (1997) [Pubmed]
  24. 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. Frølund, B., Kristiansen, U., Brehm, L., Hansen, A.B., Krogsgaard-Larsen, P., Falch, E. J. Med. Chem. (1995) [Pubmed]
  25. Nigral actions of GABA agonists are enhanced by chronic fluphenazine and differentiated by concomitant flurazepam. Coward, D.M. Psychopharmacology (Berl.) (1982) [Pubmed]
  26. Bicuculline-sensitive and insensitive effects of THIP on the binding of [3H]flunitrazepam. Zarkovsky, A.M. Neuropharmacology (1987) [Pubmed]
  27. Phencyclidine receptors in rat brain cortex. Mendelsohn, L.G., Kerchner, G.A., Kalra, V., Zimmerman, D.M., Leander, J.D. Biochem. Pharmacol. (1984) [Pubmed]
  28. Characterization of susceptibility to audiogenic seizures in ethanol-dependent rats after microinjection of gamma-aminobutyric acid (GABA) agonists into the inferior colliculus, substantia nigra or medial septum. Frye, G.D., McCown, T.J., Breese, G.R. J. Pharmacol. Exp. Ther. (1983) [Pubmed]
  29. Paradoxical blockade of a muscimol response by THIP, a GABA agonist and also by GABA-transaminase inhibitors. Menon, M.K. Neuropharmacology (1981) [Pubmed]
  30. The GABAA receptor agonist THIP alters the EEG in waking and sleep of mice. Vyazovskiy, V.V., Kopp, C., Bösch, G., Tobler, I. Neuropharmacology (2005) [Pubmed]
  31. Steroid withdrawal in the mouse results in anxiogenic effects of 3alpha,5beta-THP: a possible model of premenstrual dysphoric disorder. Smith, S.S., Ruderman, Y., Frye, C., Homanics, G., Yuan, M. Psychopharmacology (Berl.) (2006) [Pubmed]
  32. Induction of low-affinity GABAA receptors by the GABA-agonist THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) in cultured rat cerebellar granule cells is prevented by inhibition of polyamine biosynthesis. Abraham, J.H., Seiler, N., Schousboe, A. J. Neurosci. Res. (1994) [Pubmed]
  33. Synthesis and pharmacological evaluation of cis-2,3,3a,4,5,6,7,7a-octahydro-3-oxoisoxazolo[5,4-c]pyridine: a structural analogue of the GABA agonist THIP. Nordmann, R., Graff, P., Maurer, R., Gähwiler, B.H. J. Med. Chem. (1985) [Pubmed]
  34. Inducing anesthesia with a GABA analog, THIP. Cheng, S.C., Brunner, E.A. Anesthesiology (1985) [Pubmed]
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