Journal Article

Structure of the dopamine D2 receptor in complex with the antipsychotic drug spiperone

Shimamura, Tatsuro, Nakane, Takanori, Shiimura, Yuki, Yamanaka, Yasuaki, Kimura, Kanako Terakado, Im, Dohyun, Yamashita, Ayumi, Inoue, Asuka, Tanaka, Tomoyuki, Kadji, Francois Marie Ngako, Mori, Chihiro, Nomura, Norimichi, Asada, Hidetsugu, Nango, Eriko, Iwata, So, Tono, Kensuke, Fujiwara, Takaaki, Uemura, Tomoko, Aoki, Junken

2020

Overview

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

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 101/1 / 631/45/612/194 / 631/535 / 631/535/1266 / 82/80 / 82/83 / Antipsychotics / Binding / Conformation / Crystal structure / Dopamine / Dopamine D2 receptors / G protein-coupled receptors / Haloperidol / Humanities and Social Sciences / Inverse agonists / Mental disorders / multidisciplinary / Psychotropic drugs / Receptors / Risperidone / Schizophrenia / Science / Science (multidisciplinary) / Selectivity / Serotonin / Serotonin S2 receptors / Spiperone / Therapeutic targets