These authors contributed equally to this work.
Structure–Activity Relationships of Quinoxaline-Based 5-HT3A and 5-HT3AB Receptor-Selective Ligands
Version of Record online: 2 MAY 2013
© 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Volume 8, Issue 6, pages 946–955, June 2013
How to Cite
Thompson, A. J., Verheij, M. H. P., van Muijlwijk-Koezen, J. E., Lummis, S. C. R., Leurs, R. and de Esch, I. J. P. (2013), Structure–Activity Relationships of Quinoxaline-Based 5-HT3A and 5-HT3AB Receptor-Selective Ligands. ChemMedChem, 8: 946–955. doi: 10.1002/cmdc.201300032
- Issue online: 24 MAY 2013
- Version of Record online: 2 MAY 2013
- Manuscript Revised: 15 MAR 2013
- Manuscript Received: 22 JAN 2013
- Funded Access
- Wellcome Trust. Grant Number: 081925
- Cys loops;
- 5-HT3 receptors;
Until recently, discriminating between homomeric 5-HT3A and heteromeric 5-HT3AB receptors was only possible with ligands that bind in the receptor pore. This study describes the first series of ligands that can discriminate between these receptor types at the level of the orthosteric binding site. During a recent fragment screen, 2-chloro-3-(4-methylpiperazin-1-yl)quinoxaline (VUF10166) was identified as a ligand that displays an 83-fold difference in [3H]granisetron binding affinity between 5-HT3A and 5-HT3AB receptors. Fragment hit exploration, initiated from VUF10166 and 3-(4-methylpiperazin-1-yl)quinoxalin-2-ol, resulted in a series of compounds with higher affinity at either 5-HT3A or 5-HT3AB receptors. These ligands reveal that a single atom is sufficient to change the selectivity profile of a compound. At the extremes of the new compounds were 2-amino-3-(4-methylpiperazin-1-yl)quinoxaline, which showed 11-fold selectivity for the 5-HT3A receptor, and 2-(4-methylpiperazin-1-yl)quinoxaline, which showed an 8.3-fold selectivity for the 5-HT3AB receptor. These compounds represent novel molecular tools for studying 5-HT3 receptor subtypes and could help elucidate their physiological roles.