Structure–Activity Relationships of Quinoxaline-Based 5-HT(3)A and 5-HT(3)AB Receptor-Selective Ligands

Until recently, discriminating between homomeric 5-HT(3)A and heteromeric 5-HT(3)AB 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 [(3)H]granisetron binding affinity between 5-HT(3)A and 5-HT(3)AB 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-HT(3)A or 5-HT(3)AB 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-HT(3)A receptor, and 2-(4-methylpiperazin-1-yl)quinoxaline, which showed an 8.3-fold selectivity for the 5-HT(3)AB receptor. These compounds represent novel molecular tools for studying 5-HT(3) receptor subtypes and could help elucidate their physiological roles.