Dihydromuscimol

Last updated

Dihydromuscimol
(S)-Dihydromuscimol.svg (R)-Dihydromuscimol.svg
Left: (S)-dihydromuscimol
Right: (R)-dihydromuscimol
Clinical data
Other namesDHM; 4,5-Dihydromuscimol
Drug class GABAA receptor agonist; GABA reuptake inhibitor
ATC code
  • None
Identifiers
  • 5-(aminomethyl)-1,2-oxazolidin-3-one
CAS Number
PubChem CID
ChemSpider
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C4H8N2O2
Molar mass 116.120 g·mol−1
3D model (JSmol)
  • C1C(ONC1=O)CN
  • InChI=1S/C4H8N2O2/c5-2-3-1-4(7)6-8-3/h3H,1-2,5H2,(H,6,7)
  • Key:ZHCZZTNIHDWRNS-UHFFFAOYSA-N

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 2 Krogsgaard-Larsen P, Frølund B, Liljefors T, Ebert B (October 2004). "GABAA agonists and partial agonists: THIP (Gaboxadol) as a non-opioid analgesic and a novel type of hypnotic". Biochem Pharmacol. 68 (8): 1573–1580. 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. ↑ Rahbaek L, Christophersen C (2001). "The isoxazole alkaloids". Alkaloids Chem Biol. The Alkaloids: Chemistry and Biology. 57: 185–233. 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. 1 2 Krogsgaard-Larsen P, Hjeds H, Curtis DR, Lodge D, Johnston GA (June 1979). "Dihydromuscimol, thiomuscimol and related heterocyclic compounds as GABA analogues". J Neurochem. 32 (6): 1717–1724. doi:10.1111/j.1471-4159.1979.tb02284.x. PMID   448364.
  4. 1 2 Rivera-Illanes D, Recabarren-Gajardo G (September 2024). "Classics in Chemical Neuroscience: Muscimol". ACS Chem Neurosci. 15 (18): 3257–3269. doi:10.1021/acschemneuro.4c00304. PMID   39254100.
  5. ↑ Krogsgaard-Larsen P, Frølund B, Kristiansen U, Frydenvang K, Ebert B (1997). "GABAA and GABAB receptor agonists, partial agonists, antagonists and modulators: design and therapeutic prospects". European Journal of Pharmaceutical Sciences. 5 (6): 355–384. 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. 1 2 Petersen JG, Bergmann R, Krogsgaard-Larsen P, Balle T, Frølund B (June 2014). "Probing the orthosteric binding site of GABAA receptors with heterocyclic GABA carboxylic acid bioisosteres". Neurochem Res. 39 (6): 1005–1015. 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. 1 2 Høg S, Greenwood JR, Madsen KB, Larsson OM, Frølund B, Schousboe A, et al. (2006). "Structure-activity relationships of selective GABA uptake inhibitors". Curr Top Med Chem. 6 (17): 1861–1882. 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. 1 2 3 Krogsgaard-Larsen P, Nielsen L, Falch E, Curtis DR (November 1985). "GABA agonists. Resolution, absolute stereochemistry, and enantioselectivity of (S)-(+)- and (R)-(-)-dihydromuscimol". J Med Chem. 28 (11): 1612–1617. doi:10.1021/jm00149a012. PMID   2999396.
  9. ↑ Krogsgaard-Larsen P, Falch E (August 1981). "GABA agonists. Development and interactions with the GABA receptor complex". Mol Cell Biochem. 38 Spec No (Pt 1): 129–146. doi:10.1007/BF00235692. PMID   6270544.


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