4-PIOL

4-PIOL, also known as 5-(4-piperidyl)isoxazol-3-ol, is a GABA_A 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]

4-PIOL

Clinical data
Drug class	GABAA receptor partial agonist
ATC code	None
Identifiers
IUPAC name 5-piperidin-4-yl-1,2-oxazol-3-one
CAS Number	132033-91-1
PubChem CID	125520
ChemSpider	111666
KEGG	C13710
ChEBI	CHEBI:34433
ChEMBL	ChEMBL311761
CompTox Dashboard (EPA)	DTXSID70157318
Chemical and physical data
Formula	C8H12N2O2
Molar mass	168.196 g·mol−1
3D model (JSmol)	Interactive image
SMILES C1CNCCC1C2=CC(=O)NO2
InChI 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

The drug acts specifically as a low-affinity and low-efficacy partial agonist of the GABA_A receptor.^{[1][2][3][4][5]} Its affinity (IC₅₀Tooltip half-maximal inhibitory concentration) for the GABA_A 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 GABA_A 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 GABA_A 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 GABA_A receptor (binding IC₅₀ = 49; K_i = 90 nM; functional IC₅₀ = 370 nM).^{[7][8][2][12][14]} It has been said to be markedly more potent than the standard GABA_A receptor antagonist gabazine.^[2][8]