Chemistry:4-PIOL

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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 (IC50) 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

  • Thio-4-PIOL
  • Piperidine-4-sulphonic acid (P4S)

References

  1. ↑ 1.0 1.1 1.2 1.3 "GABA(A) receptor ligands and their therapeutic potentials". Current Topics in Medicinal Chemistry 2 (8): 817–832. August 2002. doi:10.2174/1568026023393525. PMID 12171573. 
  2. ↑ 2.0 2.1 2.2 2.3 "Specific GABA(A) agonists and partial agonists". Chemical Record 2 (6): 419–430. 2002. doi:10.1002/tcr.10040. PMID 12469353. 
  3. ↑ 3.0 3.1 3.2 "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. 72. 2015. pp. 201–227. doi:10.1016/bs.apha.2014.10.003. ISBN 978-0-12-802660-1. 
  4. ↑ 4.0 4.1 4.2 4.3 "Psychoactive Isoxazoles, Muscimol, and Isoxazole Derivatives from the Amanita (Agaricomycetes) Species: Review of New Trends in Synthesis, Dosage, and Biological Properties". International Journal of Medicinal Mushrooms 25 (9): 1–10. 2023. doi:10.1615/IntJMedMushrooms.2023049458. PMID 37824402. https://www.dl.begellhouse.com/download/article/663f425c2cc42e31/IJM-49458.pdf. 
  5. ↑ 5.0 5.1 5.2 5.3 "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. August 1995. doi:10.1021/jm00017a014. PMID 7650683. 
  6. ↑ "Classics in Chemical Neuroscience: Muscimol". ACS Chemical Neuroscience 15 (18): 3257–3269. September 2024. doi:10.1021/acschemneuro.4c00304. PMID 39254100. 
  7. ↑ 7.0 7.1 "Pharmacophore models for GABA(A) modulators: implications in CNS drug discovery". Expert Opinion on Drug Discovery 5 (5): 441–460. May 2010. doi:10.1517/17460441003789363. PMID 22823129. 
  8. ↑ 8.0 8.1 8.2 "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. 54. 2006. pp. 53–71. doi:10.1016/s1054-3589(06)54003-7. ISBN 978-0-12-032957-1. 
  9. ↑ 9.0 9.1 9.2 "GABA(A) receptor channel pharmacology". Current Pharmaceutical Design 11 (15): 1867–1885. 2005. doi:10.2174/1381612054021024. PMID 15974965. 
  10. ↑ "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. May 1987. PMID 2855566. 
  11. ↑ "Muscimol as an ionotropic GABA receptor agonist". Neurochemical Research 39 (10): 1942–1947. October 2014. doi:10.1007/s11064-014-1245-y. PMID 24473816. 
  12. ↑ 12.0 12.1 "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. June 2002. doi:10.1021/jm020027o. PMID 12036354. 
  13. ↑ "Developing New 4-PIOL and 4-PHP Analogues for Photoinactivation of γ-Aminobutyric Acid Type A Receptors". ACS Chemical Neuroscience 10 (11): 4669–4684. November 2019. doi:10.1021/acschemneuro.9b00478. PMID 31589403. https://curis.ku.dk/portal/da/publications/developing-new-4piol-and-4php-analogues-for-photoinactivation-of-aminobutyric-acid-type-a-receptors(7767619f-c9a1-4f0a-a72d-c500e046ec5d).html. 
  14. ↑ "A novel class of potent 3-isoxazolol GABA(A) antagonists: design, synthesis, and pharmacology". Journal of Medicinal Chemistry 43 (26): 4930–4933. December 2000. doi:10.1021/jm000371q. PMID 11150163. 

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See also
Receptor/signaling modulators
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