4-PIOL, also known as 5-(4-piperidyl)isoxazol-3-ol, is a GABA<sub>A</sub> receptor agonist that was derived from THIP (gaboxadol). It is a non-ring-fused analogue of THIP and is also closely structurally related to the Amanita muscaria alkaloid muscimol and the neurotransmitter ó-aminobutyric acid (GABA).
The drug acts specifically as a low-affinity and low-efficacy partial agonist of the GABA<sub>A</sub> receptor. Its affinity () for the GABA<sub>A</sub> receptor is 6âÂÂ9üM, whereas that of muscimol is 6nM, of THIP is 92âÂÂ130nM, and of GABA is 18nM. 4-PIOL has a predominantly antagonistic profile, but can also act as a high-efficacy partial agonist in some systems. It does not appear to desensitize GABA<sub>A</sub> 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. Potent GABA<sub>A</sub> receptor modulators, including other partial agonists as well as antagonists, have been derived via structural modification of 4-PIOL. One notable derivative of 4-PIOL, the antagonist 4-Naph-Me-4-PIOL, shows restored high affinity and potency at the GABA<sub>A</sub> receptor (binding = 49; K<sub>i</sub> = 90nM; functional IC<sub>50</sub> = 370nM). It has been said to be markedly more potent than the standard GABA<sub>A</sub> receptor antagonist gabazine.