4-PIOL
4-PIOL, also known as 5-(4-piperidyl)isoxazol-3-ol, is a GABAA 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 γ-aminobutyric acid (GABA).
The drug acts specifically as a low-affinity and low-efficacy partial agonist of the GABAA receptor. 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. 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 GABAA 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 GABAA 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 GABAA receptor (binding IC50 = 49; Ki = 90 nM; functional IC50 = 370 nM). It has been said to be markedly more potent than the standard GABAA receptor antagonist gabazine.