Muscimol as an Ionotropic GABA Receptor Agonist

@article{Johnston2014MuscimolAA,
  title={Muscimol as an Ionotropic GABA Receptor Agonist},
  author={Graham A. R. Johnston},
  journal={Neurochemical Research},
  year={2014},
  volume={39},
  pages={1942-1947}
}
  • G. Johnston
  • Published 29 January 2014
  • Biology, Chemistry
  • Neurochemical Research
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… 
GABA Receptors: Pharmacological Potential and Pitfalls.
TLDR
The aim of this review is to briefly summarize the key pharmacological properties of GABA receptors, and to present selected novel findings with the potential to open new perspectives in the development of more effective therapeutic strategies.
Pharmacological characterization of the excitatory ‘Cys‐loop’ GABA receptor family in Caenorhabditis elegans
TLDR
Using a panel of compounds that differentially activate and modulate ionotropic GABA receptors, this work investigated the agonist binding site and allosteric modulation of EXP‐1 and LGC‐35.
MmTX1 and MmTX2 from coral snake venom potently modulate GABAA receptor activity
TLDR
The first potent GABAA receptor-targeting toxins, to the authors' knowledge, are identified in snake venom, which provides a conceptual example for discovering novel ligands to study this receptor family, both functionally and structurally.
Gamma‐aminobutyric acidA receptor agonist, muscimol, increases KiSS‐1 gene expression in hypothalamic cell models
TLDR
The direct action of the gamma‐aminobutyric acid (GABA)A receptor agonist on kisspeptin‐expressing neuronal cells was examined and it was found that the receptor agonists act as a ‘spatially aggregating force’ to regulatekisspeptin levels.
Cryo-EM structure of the benzodiazepine-sensitive α1β1γ2S tri-heteromeric GABAA receptor in complex with GABA
TLDR
This work presents the structure of a tri-heteromeric α1β1γ2SEM GABAA receptor in complex with GABA, determined by single particle cryo-EM at 3.1–3.8 Å resolution, elucidating molecular principles of receptor assembly and agonist binding and providing a pathway to structural studies of heteromeric GAB AA receptors and a framework for rational design of novel therapeutic agents.
Unsaturated Analogues of the Neurotransmitter GABA: trans-4-Aminocrotonic, cis-4-Aminocrotonic and 4-Aminotetrolic Acids
  • G. Johnston
  • Biology, Chemistry
    Neurochemical Research
  • 2015
TLDR
Findings indicate that GABA activates GABAA receptors in extended conformations and GABAC receptors in folded conformations, which are important for the molecular modelling of ionotropic GABA receptors and to the development of new agents acting selectively on these receptors.
Ion Channels as Targets for Plant-Derived Drugs
TLDR
The three isoforms of glutamate receptors and the action of some psychoactive compounds, e.g. ketamine and PCP, are described and TRPV receptors are briefly touched in connection with their sensing of heat, inflammatory cytokines and theaction of capsaicin.
Simultaneous intrathecal injection of muscimol and endomorphin‐1 alleviates neuropathic pain in rat model of spinal cord injury
TLDR
Investigation of the analgesic effect of simultaneous administration of GABA agonist and endomorphin‐1 on neuropathic pain in rat model of spinal cord injury (SCI) finds that combination therapy seems to be an appropriate solution for alleviation of chronic pain and reducing the side effects.
The Isoxazole Ring and Its N‐Oxide: A Privileged Core Structure in Neuropsychiatric Therapeutics
TLDR
Various drug‐like isoxazol(in)es and their structural features and efficiency, modified through scaffold hopping, are described and discussed in the context of treating neuropsychiatric conditions.
Cryo-EM structure of the benzodiazepine-sensitive α1β1γ2 heterotrimeric GABAA receptor in complex with GABA illuminates mechanism of receptor assembly and agonist binding
TLDR
This work provides a pathway to structural studies of heteromeric GABAA receptors and a framework for the rational design of novel therapeutic agents, elucidating the molecular principles of receptor assembly and agonist binding.
...
...

References

SHOWING 1-10 OF 59 REFERENCES
Advantages of an antagonist: bicuculline and other GABA antagonists
TLDR
Bicuculline became the benchmark antagonist for what became known as GABAA receptors, but not all ionotropic GABA receptors are susceptible to bicUCulline, and there are still surprises in store as the study of GABA receptors evolves.
A new class of GABA agonist
TLDR
The action of these compounds as GABA agonists provides indirect evidence that GABA interacts with bicuculline-sensitive postsynaptic receptors in the cat spinal cord in a partially extended and almost planar conformation.
Use of 3H-muscimol for GABA receptor studies
TLDR
Evidence of the binding of 3H-muscimol by brain tissue is presented, comparing binding by membrane preparations in vitro with retention of 3 H-musCimol after intravenous administration, and the ability of muscIMol to alter evoked release of GABA by synaptosomes is verified.
Aza-THIP and related analogues of THIP as GABA C antagonists.
Neurochemicals for the Investigation of GABAC Receptors
TLDR
A variety of neurochemicals that have been shown to be useful in distinguishing GABAC receptors from other receptors for the major inhibitory neurotransmitter GABA are described.
Diazepam stimulates the binding of GABA and muscimol but not thip to rat brain membranes
The GABAA agonist THIP (gaboxadol) increases non‐REM sleep and enhances delta activity in the rat
TLDR
The effects of THIP on sleep resemble those reported earlier for the GABAA agonist muscimol and are dissimilar from those induced by benzodiazepine-agonistic modulators of GAB AA receptors, indicating that agonists and agonistic modulator of GabAA receptors affect sleep differentially.
Physiological and behavioral studies with muscimol
TLDR
Behavioral studies with muscimol remain difficult to interpret in terms of central GABAergic systems, especially since muscIMol is extensively metabolized and since it appears to interact with membrane sites other than GABA receptors.
...
...