Structures of the 5-HT_2A receptor in complex with the antipsychotics risperidone and zotepine

Many drugs target the serotonin 2A receptor (5-HT_2AR), including second-generation antipsychotics that also target the dopamine D₂ receptor (D₂R). These drugs often produce severe side effects due to non-selective binding to other aminergic receptors. Here, we report the structures of human 5-HT_2AR in complex with the second-generation antipsychotics risperidone and zotepine. These antipsychotics effectively stabilize the inactive conformation by forming direct contacts with the residues at the bottom of the ligand-binding pocket, the movements of which are important for receptor activation. 5-HT_2AR is structurally similar to 5-HT_2CR but possesses a unique side-extended cavity near the orthosteric binding site. A docking study and mutagenic studies suggest that a highly 5-HT_2AR-selective antagonist binds the side-extended cavity. The conformation of the ligand-binding pocket in 5-HT_2AR significantly differs around extracellular loops 1 and 2 from that in D₂R. These findings are beneficial for the rational design of safer antipsychotics and 5-HT_2AR-selective drugs.