A new class of selective, non-basic 5-HT2A receptor antagonists

Based on an existing series of 5-HT2A receptor ligands containing a basic nitrogen, we designed a non-basic lead that had reduced affinity for both the 5-HT2A receptor and the IKr potassium channel. The present paper describes the development of this lead to a novel series of non-basic piperidine sulfonamides and amides that have high affinity for the 5-HT2A receptor, whilst maintaining excellent selectivity over off target activities such as the IKr channel. This work has shown that the proposed pharmacaphore model for the 5-HT2A receptor which suggests that a basic nitrogen is required for the binding of ligands is questionable.

Graphical abstractThis paper describes the design of a novel series of non-basic 5-HT2A receptor antagonists thus disproving the generally accepted view that a basic nitrogen is crucial to binding at this receptor.Figure optionsDownload full-size imageDownload as PowerPoint slide