An investigation of the pharmacology of vortioxetine at human 5-HT3 receptors

A. Roberts1, G. Grafton1, S. Larkin1, S. Butterworth1, R. Myerson2, A. J. Cooper1, N. M. Barnes1. 1College of Medical and Dental Sciences, University of Birmingham, Birmingham, UNITED KINGDOM, 2School of Chemistry, University of Birmingham, Birmingham, UNITED KINGDOM.

Introduction: Vortioxetine is a novel antidepressant that was approved by the FDA in September 2013 for use in Major Depressive Disorder (MDD). Some of the most common side-effects are emesis and diarrhoea, which may indicate activation of 5-HT3 receptors at therapeutic concentrations. Indeed, vortioxetine displays affinity for a number of 5-HT receptors including the 5-HT1B, 5-HT3, and 5-HT7 receptors, and a previous study demonstrated activation of the 5-HT3 receptor but only upon first application of the drug1. The 5-HT3 receptor is a ligand-gated ion channel expressed by neurones in the brain (e.g. chemoreceptor trigger zone) as well as in the periphery (e.g. gastrointestinal tract). Two major subtypes of the receptor have been studied in the most detail; the homomeric 5-HT3A receptor and the heteromeric 5-HT3AB receptor. The aim of this study was to further explore the interaction of vortioxetine with the 5-HT3 receptor.

Methods: Using HEK293 cell lines stably expressing either the 5-HT3A or 5-HT3AB receptor, the agonist profile of vortioxetine was investigated using fluorescent intracellular calcium assays, as previously described2. Furthermore, the interaction of vortioxetine with the orthosteric site of the 5-HT3 receptor was examined using receptor binding techniques2.

Results: In functional assays, vortioxetine behaved as a partial agonist with intrinsic efficacy of 42±3 % at 5-HT3A receptors and 37±4 % at the 5-HT3AB receptors (mean±SEM, n=4). 5-Chloroindole (5-CI; 10 µM), a 5-HT3 receptor positive allosteric modulator, increased the efficacy of vortioxetine at both the 5-HT3A receptor (to 80±6 % relative to 5-HT) and 5-HT3AB receptor (77±10 % relative to 5-HT)2 (mean±SEM, n=4). The EC50 of vortioxetine was similar at 5-HT3A and 5-HT3AB receptors (179±14 nM and 119±9 nM, respectively). Receptor binding experiments demonstrated the affinity of vortioxetine was comparable between 5-HT3A and 5-HT3AB receptors (9±1.4 and 19±2 nM, respectively; mean±SEM, n=3-4). In saturation binding experiments, vortioxetine (10-30 nM) increased the Kd of [3H]-granisetron, but had no effect on the density of labelled receptors, indicative of a competitive interaction (n=4).

Conclusion: Our studies indicate vortioxetine is a relatively high affinity competitive partial agonist at the 5-HT3 receptor. Such actions may be responsible for the emesis and/or diarrhoea experienced by some patients receiving vortioxetine.

References:

1. Bang-Anderson et al. (2011). J. Med. Chem 54: 3206–3221.

2. Newman et al. (2013). Br J Pharmacol 169: 1228–1238.