Chemistry:Dihydromuscimol

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Dihydromuscimol (DHM), or 4,5-dihydromuscimol, is a synthetic GABAA receptor agonist and GABA reuptake inhibitor which was derived from the Amanita muscaria constituent muscimol.[1][2][3] The compound is a dihydroisoxazole derivative.[4]

The compound has two enantiomeric forms. (S)-Dihydromuscimol is a selective and extremely potent GABAA receptor agonist, while (R)-dihydromuscimol is a GABA reuptake inhibitor and a weak GABAA receptor agonist.[5][6][7][8] Dihydromuscimol is equipotent to muscimol as a GABAA receptor agonist but is more potent as a GABA reuptake inhibitor.[7][8] However, (S)-dihydromuscimol is slightly more potent than muscimol as a GABAA receptor agonist.[6] The enantiomer is the most potent GABAA receptor agonist that has been discovered as of 2004.[1][8]

Dihydromuscimol was first described in the scientific literature by Povl Krogsgaard-Larsen and colleagues by 1979.[4][3] The aminomethyl side chain of dihydromuscimol may be just as susceptible to metabolism as that of muscimol, and hence the drug has not been extensively used in animal studies.[9]

See also

References

  1. ↑ 1.0 1.1 "GABAA agonists and partial agonists: THIP (Gaboxadol) as a non-opioid analgesic and a novel type of hypnotic". Biochem Pharmacol 68 (8): 1573–1580. October 2004. doi:10.1016/j.bcp.2004.06.040. PMID 15451401. "Muscimol, a constituent of the mushroom Amanita muscaria, has been extensively used as a lead for the design of different classes of GABA analogues (Fig. 2). The 3-isoxazolol carboxyl group bioisostere of muscimol can be replaced by a 3-isothiazolol or 3-hydroxyisoxazoline group to give thiomuscimol and dihydromuscimol, respectively, without significant loss of GABAA receptor agonism [36]. (S)-Dihydromuscimol is the most potent GABAA agonist so far described [37]. The structurally related muscimol analogues, isomuscimol and azamuscimol, on the other hand are virtually inactive, emphasizing the very strict structural constraints imposed on agonist molecules by the GABAA receptors [36].". 
  2. ↑ "The isoxazole alkaloids". Alkaloids Chem Biol. The Alkaloids: Chemistry and Biology 57: 185–233. 2001. doi:10.1016/s0099-9598(01)57004-2. ISBN 978-0-12-469557-3. PMID 11705121. "The analog dihydromuscimol or 5-aminomethylisoxazolin-3-ol has been one of the derivatives extensively investigated for its physiological properties. It has not so far been found in nature (75).". 
  3. ↑ 3.0 3.1 "Dihydromuscimol, thiomuscimol and related heterocyclic compounds as GABA analogues". J Neurochem 32 (6): 1717–1724. June 1979. doi:10.1111/j.1471-4159.1979.tb02284.x. PMID 448364. 
  4. ↑ 4.0 4.1 "Classics in Chemical Neuroscience: Muscimol". ACS Chem Neurosci 15 (18): 3257–3269. September 2024. doi:10.1021/acschemneuro.4c00304. PMID 39254100. 
  5. ↑ "GABAA and GABAB receptor agonists, partial agonists, antagonists and modulators: design and therapeutic prospects". European Journal of Pharmaceutical Sciences 5 (6): 355–384. 1997. doi:10.1016/S0928-0987(97)10009-4. "Dihydromuscimol is a more rigid analogue of GABA, and whilst (S)-dihydromuscimol is a selective and extremely potent GABA A agonist, (R)-dihydromuscimol is a weak GABAA agonist and an inhibitor of GABA uptake (Krogsgaard-Larsen et al., 1986).". 
  6. ↑ 6.0 6.1 "Probing the orthosteric binding site of GABAA receptors with heterocyclic GABA carboxylic acid bioisosteres". Neurochem Res 39 (6): 1005–1015. June 2014. doi:10.1007/s11064-013-1226-6. PMID 24362592. "Muscimol, which has been widely used in the study of GABAAR, and the analogues (RS)-dihydromuscimol and thiomuscimol all display potencies for the GABAAR in the low nanomolar range (Table 1). The two enantiomers of dihydromuscimol display different pharmacological properties. The (S)-enantiomer shows high affinity for the GABAAR, whereas the inhibition of GABA uptake via GABA transporters displayed by dihydromuscimol proved to reside exclusively in the R-enantiomer [32]. [...] Relative agonist potencies at the GABAAR of the heterocylic muscimol analogues are (S)-dihydromuscimol > muscimol > thiomuscimol > 4-AHP >> azamuscimol as shown in Table 1.". 
  7. ↑ 7.0 7.1 "Structure-activity relationships of selective GABA uptake inhibitors". Curr Top Med Chem 6 (17): 1861–1882. 2006. doi:10.2174/156802606778249801. PMID 17017962. "4,5-Dihydromuscimol is equipotent with muscimol at the GABAA receptor, and it is more potent as an inhibitor of neuronal than glial GABA uptake systems [39]. The enantiomers of dihydromuscimol showed different pharmacology. The uptake activity resides with the (R)-enantiomer, unlike the GABAA receptor binding affinity conferred by the (S)- enantiomer. (R)-Dihydromuscimol displays a weak preference for neuronal uptake systems [27].". 
  8. ↑ 8.0 8.1 8.2 "GABA agonists. Resolution, absolute stereochemistry, and enantioselectivity of (S)-(+)- and (R)-(-)-dihydromuscimol". J Med Chem 28 (11): 1612–1617. November 1985. doi:10.1021/jm00149a012. PMID 2999396. 
  9. ↑ "GABA agonists. Development and interactions with the GABA receptor complex". Mol Cell Biochem 38 Spec No (Pt 1): 129–146. August 1981. doi:10.1007/BF00235692. PMID 6270544. 

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See also
Receptor/signaling modulators
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