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

Many drugs target the serotonin 2A receptor (5-HTR), including second-generation antipsychotics that also target the dopamine D receptor (DR). These drugs often produce severe side effects due to non-selective binding to other aminergic receptors. Here, we report the structures of human 5-HTR 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-HTR is structurally similar to 5-HTR but possesses a unique side-extended cavity near the orthosteric binding site. A docking study and mutagenic studies suggest that a highly 5-HTR-selective antagonist binds the side-extended cavity. The conformation of the ligand-binding pocket in 5-HTR significantly differs around extracellular loops 1 and 2 from that in DR. These findings are beneficial for the rational design of safer antipsychotics and 5-HTR-selective drugs.