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Muscimol as an Ionotropic GABA Receptor Agonist

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Abstract

Muscimol, a psychoactive isoxazole from Amanita muscaria and related mushrooms, has proved to be a remarkably selective agonist at ionotropic receptors for the inhibitory neurotransmitter GABA. This historic overview highlights the discovery and development of muscimol and related compounds as a GABA agonist by Danish and Australian neurochemists. Muscimol is widely used as a ligand to probe GABA receptors and was the lead compound in the development of a range of GABAergic agents including nipecotic acid, tiagabine, 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol, (Gaboxadol®) and 4-PIOL.

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References

  1. Wieland T (1968) Poisonous principles of mushrooms of the genus Amanita. Science 159:946–952

    Article  PubMed  CAS  Google Scholar 

  2. Wasson RG (1968) Soma: Divine Mushroom of Immortality. Harcourt Brace Jovanovich, New York

    Google Scholar 

  3. DeFeudis FV (1980) Physiological and behavioral studies with muscimol. Neurochem Res 5:1047–1068

    Article  PubMed  CAS  Google Scholar 

  4. Eugster CH, Takemoto T (1967) Zür Nomenclature der neuen Verbindungen aus Amanita-Arten. Helv Chim Acta 50:126–127

    Article  PubMed  CAS  Google Scholar 

  5. Johnston GAR, Curtis DR, De Groat WC, Duggan AW (1968) Central actions of ibotenic acid and muscimol. Biochem Pharmacol 17:2488–2489

    Article  PubMed  CAS  Google Scholar 

  6. Curtis DR, Hösli L, Johnston GAR (1967) Inhibition of spinal neurons by glycine. Nature 215:1502–1503

    Article  PubMed  CAS  Google Scholar 

  7. Curtis DR, Duggan AW, Felix D, Johnston GAR (1971) Bicuculline, an antagonist of GABA and synaptic inhibition in the spinal cord of the cat. Brain Res 32:69–96

    Article  PubMed  CAS  Google Scholar 

  8. Johnston GAR, GABA chemistry: Analogs of GABA as therapeutic and investigational agents, in GABA In The Nervous System: The View At Fifty Years, D.L. Martin and R. Olsen, Editors. 2000, Lippincott Williams and Wilkins: Philadelphia. p. 65-80.

  9. Brehm L, Hjeds H, Krogsgaard-Larsen P (1972) The structre of muscimol, a GABA analogue of restricted conformation. Acta Chem Scand 26:1298–1299

    Article  PubMed  CAS  Google Scholar 

  10. Curtis DR (2006) David R. Curtis Autobiography. The History of Neuroscience in Autobiography 5:171–225

    Google Scholar 

  11. Krogsgaard-Larsen P, Johnston GAR, Curtis DR, Game CJA, McCulloch RM (1975) Structure and biological activity of a series of conformationally restricted analogues of GABA. J Neurochem 25:803–809

    Article  PubMed  CAS  Google Scholar 

  12. Chebib M, Johnston GAR (2000) GABA-activated ligand gated ion channels: medical chemistry and molecular biology. J Med Chem 43:1427–1447

    Article  PubMed  CAS  Google Scholar 

  13. Johnston GAR (2013) Advantages of an antagonist: bicuculline and other GABA antagonists. Br J Pharmacol 169:328–336

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  14. Beart PM, Curtis DR, Johnston GAR (1971) 4-Aminotetrolic acid: new conformational-restricted analogue of γ-aminobutyric acid. Nature - New Biology 234:80–81

    Article  PubMed  CAS  Google Scholar 

  15. Johnston GAR, Curtis DR, Beart PM, Game CJA, McCulloch RM, Twitchin B (1975) Cis- and trans-4-aminocrotonic acid as GABA analogues of restricted conformation. J Neurochem 24:157–160

    Article  PubMed  CAS  Google Scholar 

  16. Johnston GAR, Chebib M, Hanrahan JR, Mewett KN (2010) Neurochemicals for the investigation of GABAC receptors. Neurochem Res 35:1970–1977

    Article  PubMed  CAS  Google Scholar 

  17. Snodgrass SR (1978) Use of 3H-muscimol for GABA receptor studies. Nature 273:392–394

    Article  PubMed  CAS  Google Scholar 

  18. Krogsgaard-Larsen P, Johnston GAR (1978) Structure-activity studies on the inhibition of GABA binding to rat brain membranes by muscimol and related compounds. J Neurochem 30:1377–1382

    Article  PubMed  CAS  Google Scholar 

  19. Johnston GAR (1971) Muscimol and the uptake of γ-aminobutyric acid by rat brain slices. Psychopharmacologia 22:230–233

    Article  PubMed  CAS  Google Scholar 

  20. Johnston GAR, Kennedy SM, Lodge D (1978) Muscimol uptake, release and binding in rat brain slices. J Neurochem 31:1519–1523

    Article  PubMed  CAS  Google Scholar 

  21. Woodward RM, Polenzani L, Miledi R (1993) Characterization of bicuculline/baclofen-insensitive (ρ-like) γ-aminobutyric acid receptors expressed in Xenopus oocytes. II. Pharmacology of γ-aminobutyric acidA and γ-aminobutyric acidB receptor agonists and antagonists. Mol Pharmacol 43:609–625

    PubMed  CAS  Google Scholar 

  22. Ebert B, Thompson SA, Saounatsou K, McKernan R, Krogsgaard-Larsen P, Wafford KA (1997) Differences in agonist/antagonist binding affinity and receptor transduction using recombinant human γ-aminobutyric acid type A receptors. Mol Pharmacol 52:1150–1156

    PubMed  CAS  Google Scholar 

  23. Storustovu SI, Ebert B (2006) Pharmacological characterization of agonists at delta-containing GABAA receptors: Functional selectivity for extrasynaptic receptors is dependent on the absence of gamma2. J Pharmacol Exp Ther 316:1351–1359

    Article  PubMed  CAS  Google Scholar 

  24. Mortensen M, Ebert B, Wafford K, Smart TG (2010) Distinct activities of GABA agonists at synaptic- and extrasynaptic-type GABAA receptors. J Physiol 588:1251–1268

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  25. DeFeudis FV (1980) Binding stuides with muscimol; Relation to synaptic γ-aminobutrate receptors. Neuroscience 5:675–688

    Article  PubMed  CAS  Google Scholar 

  26. Baur R, Sigel E (2003) On high- and low-affinity agonist sites in GABAA receptors. J Neurochem 87:325–332

    Article  PubMed  CAS  Google Scholar 

  27. Andrews PR, Johnston GAR (1979) Conformational analysis of muscimol, a GABA agonist. J Theor Biol 79:263–273

    Article  PubMed  CAS  Google Scholar 

  28. Bergmann R, Kongsbak K, Sorensen PL, Sander T, Balle T (2013) A unified model of the GABA(A) receptor comprising agonist and benzodiazepine binding sites. PLoS ONE [Electronic Resource] 8:e52323

    Article  CAS  Google Scholar 

  29. Karim N, Wellendorph P, Absalom N, Bang LH, Jensen ML, Hansen MM, Lee HJ, Johnston GAR, Hanrahan JR, Chebib M (2012) Low nanomolar GABA effects at extrasynaptic alpha4beta1/beta3delta GABAA receptor subtypes indicate a different binding mode for GABA at these receptors. Biochem Pharmacol 84:549–557

    Article  PubMed  CAS  Google Scholar 

  30. Krogsgaard-Larsen P, Johnston GAR (1975) Inhibition of GABA uptake in rat brain slices by nipecotic acid, various isoxazoles and related compounds. J Neurochem 25:797–802

    Article  PubMed  CAS  Google Scholar 

  31. Brehm L, Krogsgaard-Larsen P, Johnston GAR, Schaumburg K (1976) X-Ray crystallographic and proton magnetic resonance spectorscopic investigations of nipecotic acid, a potent inhibitor of γ-aminobutyric acid (GABA) uptake. Acta Chem. Scand. B 30:542–548

    Article  Google Scholar 

  32. Johnston GAR, Stephanson AL, Twitchin B (1976) Uptake and release of nipecotic acid by rat brain slices. J Neurochem 26:83–87

    PubMed  CAS  Google Scholar 

  33. Johnston GAR, Krogsgaard-Larsen P, Stephanson AL, Twitchin B (1976) Inhibition of the uptake of GABA and related amino acids in rat brain slices by the optical isomers of nipecotic acid. J Neurochem 26:1029–1032

    Article  PubMed  CAS  Google Scholar 

  34. Juhasz G, Kekesi KA, Nyitral G, Dobolyl A, Krogsgaard-Larsen P, Schousboe A (1997) Differential effects of nipecotic acid and 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol on extracellular γ-aminobutyrate levels in rat thalamus. Eur J Pharmacol 331:139–144

    Article  PubMed  CAS  Google Scholar 

  35. Falch E, Perregaard J, Frølund B, Sokilde B, Buur A, Hansen LM, Frydenvang K, Brehm L, Bolvig T, Larsson OM, Sanchez C, White HS, Schousboe A, Krogsgaard LP (1999) Selective inhibitors of glial GABA uptake: synthesis, absolute stereochemistry, and pharmacology of the enantiomers of 3-hydroxy-4-amino-4,5,6,7-tetrahydro-1,2-benzisoxazole (exo-THPO) and analogues. J Med Chem 42:5402–5414

    Article  PubMed  CAS  Google Scholar 

  36. Falch E, Krogsgaard-Larsen P (1989) GABA uptake inhibitors containing mono- and diarylmethoxyalkyl N-subsitutents. Drug Design & Delivery 4:205–215

    CAS  Google Scholar 

  37. Andersen KE, Braestrup C, Gronwald FC, Jorgensen AS, Nielsen EB, Sonnewald U, Sorensen PO, Suzdak PD, Knutsen LJ (1993) The synthesis of novel GABA uptake inhibitors. 1. Elucidation of the structure-activity studies leading to the choice of (R)-1-[4,4-bis(3-methyl)-3-thienyl-3-butenyl]-3-piperidinecarboxylic acid (tiagabine) as an anticonvulsant drug candidate. J Med Chem 36:1716–1725

    Article  PubMed  CAS  Google Scholar 

  38. Borden LA, Murali Dhar TG, Smith KE, Weinshank RL, Branchek TA, Gluchowki C (1964) Tiagabine, SK&F 89976-A, CI-966, and NNC-711 are selective for the cloned GABA transporter GAT-1. Eur J Pharmacol 269:219–224

    Article  Google Scholar 

  39. Schousboe A, Madsen KK, White HS (2011) GABA transport inhibitors and seizure protection: the past and future. Future Medicinal Chemistry 3:183–187

    Article  PubMed  CAS  Google Scholar 

  40. Schousboe A, Madsen KK, Barker-Haliski ML, and White HS (2014) The GABA synapse as a target for antiepileptic drugs: a historical overview focused on GABA transporters. Neurochemical Research: in press this issue

  41. Krogsgaard-Larsen P, Johnston GAR, Lodge D, Curtis DR (1977) A new class of GABA agonist. Nature 268:53–55

    Article  PubMed  CAS  Google Scholar 

  42. Krehan D, Frølund B, Ebert B, Nielsen B, Krogsgaard-Larsen P, Johnston GAR, Chebib M (2003) Aza-THIP and related analogues of THIP as GABAC antagonists. Bioorganic and Medicinal Chemistry 11:4891–4896

    Article  PubMed  CAS  Google Scholar 

  43. Skerritt JH, Johnston GAR (1983) Diazepam stimulates the binding of GABA and muscimol but not THIP to rat brain membranes. Neurosci Lett 38:315–320

    Article  PubMed  CAS  Google Scholar 

  44. Krogsgaard-Larsen P, Frolund B, Liljefors T, Ebert B (2004) GABAA agonists and partial agonists: THIP (Gaboxadol) as a non-opioid analgesic and a novel type of hypnotic. Biochem Pharmacol 68:1573–1580

    Article  PubMed  CAS  Google Scholar 

  45. Lancel M, Faulhaber J (1996) The GABA(a) agonist THIP (gaboxadol) increases non-rem sleep and enhances delta activity in the rat. NeuroReport 7:2241–2245

    Article  PubMed  CAS  Google Scholar 

  46. Frølund B, Kristiansen U, Brehm L, Hansen AB, Krogsgaard-Larsen P, Falch E (1995) 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 38:3287–3296

    Article  PubMed  Google Scholar 

  47. Frølund B, Tagmose L, Jorgensen AT, Kristiansen U, Stensbol TB, Liljefors T, Krogsgaard-Larsen P (2003) Design and synthesis of a new series of 4-alkylated 3-isoxazolol GABA A antagonists. Eur J Med Chem 38:447–449

    Article  PubMed  Google Scholar 

  48. Hoestgaard-Jensen K, O’Connor RM, Dalby NO, Simonsen C, Finger BC, Golubeva A, Hammer H, Bergmann ML, Kristiansen U, Krogsgaard-Larsen P, Brauner-Osborne H, Ebert B, Frølund B, Cryan JF, Jensen AA (2013) The orthosteric GABAA receptor ligand Thio-4-PIOL displays distinctly different functional properties at synaptic and extrasynaptic receptors. Br J Pharmacol 170:919–932

    Article  PubMed  CAS  Google Scholar 

  49. 49. Peterson JG, Bergmann R, Krogsgaard-Larsen P, Balle T, and Frølund B (2014) Probing the orthosteric binding site of GABAA receptors with heterocyclic GABA carboxylic acid bioisosteres. Neurochemical Research:in press

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Acknowledgments

I thank my many Danish colleagues, particularly the Krogsgaard-Larsen family, for their friendship over many years. I am grateful to Phil Beart, Jane Hanrahan and Ken Mewett for their helpful comments on the manuscript.

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Authors and Affiliations

  1. Adrien Albert Laboratory of Medicinal Chemistry, School of Medical Sciences (Pharmacology), The University of Sydney, Sydney, NSW, 2006, Australia

    Graham A. R. Johnston

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  1. Graham A. R. Johnston
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Correspondence to Graham A. R. Johnston.

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Special Issue: In honor of Krogsgaard-Larsen.

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Johnston, G.A.R. Muscimol as an Ionotropic GABA Receptor Agonist. Neurochem Res 39, 1942–1947 (2014). https://doi.org/10.1007/s11064-014-1245-y

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