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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.