Abstract

The human 5-HT2 receptor subtypes have high sequence identity in their orthosteric ligand-binding domain, and many agonists are poorly selective between the S-HT(2A )and 5-HT2C subtypes. Nevertheless, their activation is associated with different pharmacological outcomes. We synthesized five phenethylamine analogs in which the benzene ring is replaced by a bulky dibenzo[b,d]furan moiety and found a couple with >70-fold 5-HT2C selectivity. Molecular docking studies of the most potent compound (5) at both receptor subtypes revealed the likely structural basis of its selectivity. Although in both cases, some crucial interactions are conserved, the change of the Ala222(5.46) residue in the 5-HT2C receptor to the larger Ser242(5.46 )in the 5-HT2A subtype, which is the only structural difference between the orthosteric binding pockets of both receptors, weakens a pi-pi stacking interaction between the dibenzofuran moiety and the important Phe(6.52) residue and breaks a hydrogen bond between the dibenzofuran oxygen and Ser(5.43) explaining the selectivity of compound 5 for the 5-HT(2C )receptor. We believe that this effect of the residue at position 5.46 merits further exploration in the search for selective 5-HT2C receptor agonists that are of considerable interest in the treatment of schizophrenia and substance abuse.