RT Journal Article SR Electronic T1 Non-Competitive Inhibition of 5-HT3 Receptors by Citral, Linalool and Eucalyptol Revealed by Non-Linear Mixed Effects Modelling JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP jpet.115.230011 DO 10.1124/jpet.115.230011 A1 Gavin E Jarvis A1 Roseli Barbosa A1 Andrew J Thompson YR 2015 UL http://jpet.aspetjournals.org/content/early/2015/12/15/jpet.115.230011.abstract AB Citral, eucalyptol and linalool are widely used as flavourings, fragrances and cosmetics. Here we examined their effects on electrophysiological and binding properties of human 5‐HT3 receptors expressed in Xenopus oocytes and HEK 293 cells respectively. Data were analysed using non-linear mixed effects modelling to enable random variance in the peak current response between oocytes to be taken into account. It showed that the oils caused an insurmountable inhibition of 5‐HT‐evoked currents (citral IC50 = 120 µM; eucalyptol = 258 µM; linalool = 141 µM) and did not compete with fluorescently labelled granisetron (G‐FL), suggesting a non‐competitive mechanism of action. Inhibition was not use‐dependent but required a 30 s pre-application. Compound washout caused a slow (~180 s) but complete recovery. Co-application of the oils with bilobalide or diltiazem indicated they did not bind at the same location as these channel blockers. Homology modelling and ligand docking predicted binding to a transmembrane cavity at the interface of adjacent subunits. LC-MS showed an essential oil extracted from Lippia alba contained 75.9% citral. This inhibited expressed 5‐HT3 receptors (IC50 = 45 µg ml‐1) and smooth muscle contractions in rat trachea (IC50 = 200 µg ml‐1) and guinea pig ileum (IC50 = 20 µg ml‐1), providing a possible mechanistic explanation for why this oil has been used to treat gastrointestinal and respiratory ailments. These results demonstrate that citral, eucalyptol and linalool inhibit 5-HT3 receptors, and their binding to a conserved cavity suggests a valuable target for novel allosteric modulators.