The compound has twoenantiomeric forms. (S)-Dihydromuscimol is aselective and extremelypotent GABAA receptor agonist, while (R)-dihydromuscimol is a GABA reuptake inhibitor and a weak GABAA receptor agonist.[5][6][7][8] Dihydromuscimol isequipotent 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]
^abKrogsgaard-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.PMID15451401.Muscimol, a constituent of the mushroomAmanita 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].
^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.ISBN978-0-12-469557-3.PMID11705121.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).
^abKrogsgaard-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.PMID448364.
^abRivera-Illanes D, Recabarren-Gajardo G (September 2024). "Classics in Chemical Neuroscience: Muscimol".ACS Chem Neurosci.15 (18):3257–3269.doi:10.1021/acschemneuro.4c00304.PMID39254100.
^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).
^abPetersen 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.PMID24362592.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.
^abHøg 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.PMID17017962.4,5-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].
^abcKrogsgaard-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.PMID2999396.
^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.PMID6270544.
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