Discovery of Benzamide Analogues as a Novel Class of 5-HT3 Receptor Agonists

A 5-HT₃ receptor agonist based on a benzamide scaffold was identified in a screening of a small commercial compound library, and an elaborate SAR study originating from this hit was performed. The design, synthesis, and functional characterisation of benzamide analogues at the 5-HT₃A receptor yielded substantial information concerning the analogues as 5-HT₃ receptor agonists. However, the potencies of the derived analogues were not significantly improved over that of the initial hit. The benzamide scaffold constitutes a novel type of 5-HT₃ receptor agonist, as it does not possess a positively charged functionality, which is essential for the binding of all orthosteric ligands to the receptor. Preliminary investigations suggest that the compounds may exert their effects on 5-HT₃ receptors by binding to an allosteric site in the receptor complex.