2,5-Disubstituted pyridines: The discovery of a novel series of 5-HT2A ligands

This report describes the effect of replacing the central basic amine present in many known 5-HT2A ligands with an aromatic residue. We targeted the isomeric phenethylpyridines 2 and 3 and these compounds proved to be excellent leads, possessing good 5-HT2A receptor binding affinity and selectivity over the 5-HT2C subtype. Optimization of one isomer led to the identification of 25, a compound with sub-nanomolar 5-HT2A affinity and selectivity over 5-HT2C of greater than 4600-fold.

This report describes the effect of replacing the central basic amine present in many known 5-HT2A ligands with an aromatic residue. We targeted the isomeric phenethylpyridines 2 and 3 and these compounds proved to be excellent leads, possessing good 5-HT2A receptor binding affinity and selectivity over the 5-HT2C subtype. Optimization of one isomer led to the identification of 25, a compound with sub-nanomolar 5-HT2A affinity and selectivity over 5-HT2C of greater than 4600-fold.Figure optionsDownload as PowerPoint slide