4-PIOL

4-PIOL
Clinical data
Drug classGABAA receptor partial agonist
ATC code
  • None
Identifiers
  • 5-piperidin-4-yl-1,2-oxazol-3-one
CAS Number
PubChem CID
ChemSpider
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC8H12N2O2
Molar mass168.196 g·mol−1
3D model (JSmol)
  • C1CNCCC1C2=CC(=O)NO2
  • InChI=1S/C8H12N2O2/c11-8-5-7(12-10-8)6-1-3-9-4-2-6/h5-6,9H,1-4H2,(H,10,11)
  • Key:YYOYGSTYWVHCJR-UHFFFAOYSA-N

4-PIOL, also known as 5-(4-piperidyl)isoxazol-3-ol, is a GABAA receptor agonist that was derived from THIP (gaboxadol).[1][2][3][4] It is a non-ring-fused analogue of THIP and is also closely structurally related to the Amanita muscaria alkaloid muscimol and the neurotransmitter γ-aminobutyric acid (GABA).[4][5][6]

The drug acts specifically as a low-affinity and low-efficacy partial agonist of the GABAA receptor.[1][2][3][4][5] Its affinity (IC50Tooltip half-maximal inhibitory concentration) for the GABAA receptor is 6–9 μM, whereas that of muscimol is 6 nM, of THIP is 92–130 nM, and of GABA is 18 nM.[7][8][5] 4-PIOL has a predominantly antagonistic profile, but can also act as a high-efficacy partial agonist in some systems.[9] It does not appear to desensitize GABAA receptors, which is in contrast to higher-efficacy agonists.[9][1] This property of 4-PIOL is thought to be related to its low-efficacy agonism.[9][1]

4-PIOL was developed by Povl Krogsgaard-Larsen and colleagues and was first described in the scientific literature by 1987.[10] Potent GABAA receptor modulators, including other partial agonists as well as antagonists, have been derived via structural modification of 4-PIOL.[4][11][3][5][12][13] One notable derivative of 4-PIOL, the antagonist 4-Naph-Me-4-PIOL, shows restored high affinity and potency at the GABAA receptor (binding IC50 = 49; Ki = 90 nM; functional IC50 = 370 nM).[7][8][2][12][14] It has been said to be markedly more potent than the standard GABAA receptor antagonist gabazine.[2][8]

See also

References

  1. ^ a b c d Frølund B, Ebert B, Kristiansen U, Liljefors T, Krogsgaard-Larsen P (August 2002). "GABA(A) receptor ligands and their therapeutic potentials". Current Topics in Medicinal Chemistry. 2 (8): 817–832. doi:10.2174/1568026023393525. PMID 12171573.
  2. ^ a b c d Krogsgaard-Larsen P, Frølund B, Liljefors T (2002). "Specific GABA(A) agonists and partial agonists". Chemical Record. 2 (6): 419–430. doi:10.1002/tcr.10040. PMID 12469353.
  3. ^ a b c Krall J, Balle T, Krogsgaard-Larsen N, Sørensen TE, Krogsgaard-Larsen P, Kristiansen U, et al. (2015). "GABAA receptor partial agonists and antagonists: structure, binding mode, and pharmacology". Diversity and Functions of GABA Receptors: A Tribute to Hanns Möhler, Part A. Advances in Pharmacology. Vol. 72. pp. 201–227. doi:10.1016/bs.apha.2014.10.003. ISBN 978-0-12-802660-1. PMID 25600372.
  4. ^ a b c d Okhovat A, Cruces W, Docampo-Palacios ML, Ray KP, Ramirez GA (2023). "Psychoactive Isoxazoles, Muscimol, and Isoxazole Derivatives from the Amanita (Agaricomycetes) Species: Review of New Trends in Synthesis, Dosage, and Biological Properties" (PDF). International Journal of Medicinal Mushrooms. 25 (9): 1–10. doi:10.1615/IntJMedMushrooms.2023049458. PMID 37824402.
  5. ^ a b c d Frølund B, Kristiansen U, Brehm L, Hansen AB, Krogsgaard-Larsen P, Falch E (August 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". Journal of Medicinal Chemistry. 38 (17): 3287–3296. doi:10.1021/jm00017a014. PMID 7650683.
  6. ^ Rivera-Illanes D, Recabarren-Gajardo G (September 2024). "Classics in Chemical Neuroscience: Muscimol". ACS Chemical Neuroscience. 15 (18): 3257–3269. doi:10.1021/acschemneuro.4c00304. PMID 39254100.
  7. ^ a b Ghoshal N, Vijayan RS (May 2010). "Pharmacophore models for GABA(A) modulators: implications in CNS drug discovery". Expert Opinion on Drug Discovery. 5 (5): 441–460. doi:10.1517/17460441003789363. PMID 22823129.
  8. ^ a b c Krogsgaard-Larsen P, Frølund B, Liljefors T (2006). "GABAA Agonists and Partial Agonists: THIP (Gaboxadol) as a Non-Opioid Analgesic and a Novel Type of Hypnotic1". GABA(A) agonists and partial agonists: THIP (Gaboxadol) as a non-opioid analgesic and a novel type of hypnotic. Advances in Pharmacology. Vol. 54. pp. 53–71. doi:10.1016/s1054-3589(06)54003-7. ISBN 978-0-12-032957-1. PMID 17175810.
  9. ^ a b c Johnston GA (2005). "GABA(A) receptor channel pharmacology". Current Pharmaceutical Design. 11 (15): 1867–1885. doi:10.2174/1381612054021024. PMID 15974965.
  10. ^ Byberg JR, Labouta IM, Falch E, Hjeds H, Krogsgaard-Larsen P, Curtis DR, et al. (May 1987). "Synthesis and biological activity of a GABAA agonist which has no effect on benzodiazepine binding and of structurally related glycine antagonists". Drug Design and Delivery. 1 (4): 261–274. PMID 2855566.
  11. ^ Johnston GA (October 2014). "Muscimol as an ionotropic GABA receptor agonist". Neurochemical Research. 39 (10): 1942–1947. doi:10.1007/s11064-014-1245-y. PMID 24473816.
  12. ^ a b Frølund B, Jørgensen AT, Tagmose L, Stensbøl TB, Vestergaard HT, Engblom C, et al. (June 2002). "Novel class of potent 4-arylalkyl substituted 3-isoxazolol GABA(A) antagonists: synthesis, pharmacology, and molecular modeling". Journal of Medicinal Chemistry. 45 (12): 2454–2468. doi:10.1021/jm020027o. PMID 12036354.
  13. ^ Mortensen M, Krall J, Kongstad KT, Brygger BM, Lenzi O, Francotte P, et al. (November 2019). "Developing New 4-PIOL and 4-PHP Analogues for Photoinactivation of γ-Aminobutyric Acid Type A Receptors". ACS Chemical Neuroscience. 10 (11): 4669–4684. doi:10.1021/acschemneuro.9b00478. PMID 31589403.
  14. ^ Frølund B, Tagmose L, Liljefors T, Stensbøl TB, Engblom C, Kristiansen U, et al. (December 2000). "A novel class of potent 3-isoxazolol GABA(A) antagonists: design, synthesis, and pharmacology". Journal of Medicinal Chemistry. 43 (26): 4930–4933. doi:10.1021/jm000371q. PMID 11150163.

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