4-PIOL

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| image = 4-PIOL.svg

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| class = GABA_A receptor partial agonist

| ATC_prefix = None

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| CAS_number = 132033-91-1

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| PubChem = 125520

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| DrugBank =

| ChemSpiderID = 111666

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| KEGG = C13710

| ChEBI = 34433

| ChEMBL = 311761

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| IUPAC_name = 5-piperidin-4-yl-1,2-oxazol-3-one

| C=8 | H=12 | N=2 | O=2

| SMILES = C1CNCCC1C2=CC(=O)NO2

| StdInChI = 1S/C8H12N2O2/c11-8-5-7(12-10-8)6-1-3-9-4-2-6/h5-6,9H,1-4H2,(H,10,11)

| StdInChIKey = YYOYGSTYWVHCJR-UHFFFAOYSA-N

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4-PIOL, also known as 5-(4-piperidyl)isoxazol-3-ol, is a GABA_A receptor agonist that was derived from THIP (gaboxadol).{{cite journal | vauthors = Frølund B, Ebert B, Kristiansen U, Liljefors T, Krogsgaard-Larsen P | title = GABA(A) receptor ligands and their therapeutic potentials | journal = Current Topics in Medicinal Chemistry | volume = 2 | issue = 8 | pages = 817–832 | date = August 2002 | pmid = 12171573 | doi = 10.2174/1568026023393525 }}{{cite journal | vauthors = Krogsgaard-Larsen P, Frølund B, Liljefors T | title = Specific GABA(A) agonists and partial agonists | journal = Chemical Record | volume = 2 | issue = 6 | pages = 419–430 | date = 2002 | pmid = 12469353 | doi = 10.1002/tcr.10040 }}{{cite book | vauthors = Krall J, Balle T, Krogsgaard-Larsen N, Sørensen TE, Krogsgaard-Larsen P, Kristiansen U, Frølund B | title = Diversity and Functions of GABA Receptors: A Tribute to Hanns Möhler, Part A | chapter = GABAA receptor partial agonists and antagonists: structure, binding mode, and pharmacology | series = Advances in Pharmacology | volume = 72 | pages = 201–227 | date = 2015 | pmid = 25600372 | doi = 10.1016/bs.apha.2014.10.003 | isbn = 978-0-12-802660-1 }}{{cite journal | vauthors = Okhovat A, Cruces W, Docampo-Palacios ML, Ray KP, Ramirez GA | title = Psychoactive Isoxazoles, Muscimol, and Isoxazole Derivatives from the Amanita (Agaricomycetes) Species: Review of New Trends in Synthesis, Dosage, and Biological Properties | journal = International Journal of Medicinal Mushrooms | volume = 25 | issue = 9 | pages = 1–10 | date = 2023 | pmid = 37824402 | doi = 10.1615/IntJMedMushrooms.2023049458 | url = https://www.dl.begellhouse.com/download/article/663f425c2cc42e31/IJM-49458.pdf }} 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).{{cite journal | vauthors = Rivera-Illanes D, Recabarren-Gajardo G | title = Classics in Chemical Neuroscience: Muscimol | journal = ACS Chemical Neuroscience | volume = 15 | issue = 18 | pages = 3257–3269 | date = September 2024 | pmid = 39254100 | doi = 10.1021/acschemneuro.4c00304 }}

The drug acts specifically as a low-affinity and low-efficacy partial agonist of the GABA_A receptor.{{cite journal | vauthors = Frølund B, Kristiansen U, Brehm L, Hansen AB, Krogsgaard-Larsen P, Falch E | title = 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 = Journal of Medicinal Chemistry | volume = 38 | issue = 17 | pages = 3287–3296 | date = August 1995 | pmid = 7650683 | doi = 10.1021/jm00017a014 }} Its affinity ({{Abbrlink|IC₅₀|half-maximal inhibitory concentration}}) for the GABA_A receptor is 6–9{{nbsp}}μM, whereas that of muscimol is 6{{nbsp}}nM, of THIP is 92–130{{nbsp}}nM, and of GABA is 18{{nbsp}}nM.{{cite journal | vauthors = Ghoshal N, Vijayan RS | title = Pharmacophore models for GABA(A) modulators: implications in CNS drug discovery | journal = Expert Opinion on Drug Discovery | volume = 5 | issue = 5 | pages = 441–460 | date = May 2010 | pmid = 22823129 | doi = 10.1517/17460441003789363 }}{{cite book | vauthors = Krogsgaard-Larsen P, Frølund B, Liljefors T | title = GABA(A) agonists and partial agonists: THIP (Gaboxadol) as a non-opioid analgesic and a novel type of hypnotic | chapter = GABAA Agonists and Partial Agonists: THIP (Gaboxadol) as a Non-Opioid Analgesic and a Novel Type of Hypnotic1 | series = Advances in Pharmacology | volume = 54 | pages = 53–71 | date = 2006 | pmid = 17175810 | doi = 10.1016/s1054-3589(06)54003-7 | isbn = 978-0-12-032957-1 }} 4-PIOL has a predominantly antagonistic profile, but can also act as a high-efficacy partial agonist in some systems.{{cite journal | vauthors = Johnston GA | title = GABA(A) receptor channel pharmacology | journal = Current Pharmaceutical Design | volume = 11 | issue = 15 | pages = 1867–1885 | date = 2005 | pmid = 15974965 | doi = 10.2174/1381612054021024 }} It does not appear to desensitize GABA_A receptors, which is in contrast to higher-efficacy agonists. This property of 4-PIOL is thought to be related to its low-efficacy agonism.

4-PIOL was developed by Povl Krogsgaard-Larsen and colleagues and was first described in the scientific literature by 1987.{{cite journal | vauthors = Byberg JR, Labouta IM, Falch E, Hjeds H, Krogsgaard-Larsen P, Curtis DR, Gynther BD | title = Synthesis and biological activity of a GABAA agonist which has no effect on benzodiazepine binding and of structurally related glycine antagonists | journal = Drug Design and Delivery | volume = 1 | issue = 4 | pages = 261–274 | date = May 1987 | pmid = 2855566 | doi = }} Potent GABA_A receptor modulators, including other partial agonists as well as antagonists, have been derived via structural modification of 4-PIOL.{{cite journal | vauthors = Johnston GA | title = Muscimol as an ionotropic GABA receptor agonist | journal = Neurochemical Research | volume = 39 | issue = 10 | pages = 1942–1947 | date = October 2014 | pmid = 24473816 | doi = 10.1007/s11064-014-1245-y }}{{cite journal | vauthors = Frølund B, Jørgensen AT, Tagmose L, Stensbøl TB, Vestergaard HT, Engblom C, Kristiansen U, Sanchez C, Krogsgaard-Larsen P, Liljefors T | title = Novel class of potent 4-arylalkyl substituted 3-isoxazolol GABA(A) antagonists: synthesis, pharmacology, and molecular modeling | journal = Journal of Medicinal Chemistry | volume = 45 | issue = 12 | pages = 2454–2468 | date = June 2002 | pmid = 12036354 | doi = 10.1021/jm020027o }}{{cite journal | vauthors = Mortensen M, Krall J, Kongstad KT, Brygger BM, Lenzi O, Francotte P, Sørensen TE, Nielsen B, Jensen AA, Smart TG, Frølund B | title = Developing New 4-PIOL and 4-PHP Analogues for Photoinactivation of γ-Aminobutyric Acid Type A Receptors | journal = ACS Chemical Neuroscience | volume = 10 | issue = 11 | pages = 4669–4684 | date = November 2019 | pmid = 31589403 | doi = 10.1021/acschemneuro.9b00478 | url = 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 }} One notable derivative of 4-PIOL, the antagonist 4-Naph-Me-4-PIOL, shows restored high affinity and potency at the GABA_A receptor (binding {{Abbr|IC₅₀|half-maximal inhibitory concentration}} = 49; K_i = 90{{nbsp}}nM; functional IC₅₀ = 370{{nbsp}}nM).{{cite journal | vauthors = Frølund B, Tagmose L, Liljefors T, Stensbøl TB, Engblom C, Kristiansen U, Krogsgaard-Larsen P | title = A novel class of potent 3-isoxazolol GABA(A) antagonists: design, synthesis, and pharmacology | journal = Journal of Medicinal Chemistry | volume = 43 | issue = 26 | pages = 4930–4933 | date = December 2000 | pmid = 11150163 | doi = 10.1021/jm000371q }} It has been said to be markedly more potent than the standard GABA_A receptor antagonist gabazine.