Structure of the dopamine D receptor in complex with the antipsychotic drug spiperone.

In addition to the serotonin 5-HT receptor (5-HTR), the dopamine D receptor (DR) is a key therapeutic target of antipsychotics for the treatment of schizophrenia. The inactive state structures of DR have been described in complex with the inverse agonists risperidone (DR) and haloperidol (DR). Here we describe the structure of human DR in complex with spiperone (DR). In DR, the conformation of the extracellular loop (ECL) 2, which composes the ligand-binding pocket, was substantially different from those in DR and DR, demonstrating that ECL2 in DR is highly dynamic. Moreover, DR exhibited an extended binding pocket to accommodate spiperone's phenyl ring, which probably contributes to the selectivity of spiperone to DR and 5-HTR. Together with DR and DR, the structural information of DR should be of value for designing novel antipsychotics with improved safety and efficacy.