A new era of rationally designed antipsychotics

Abstract

The ideal drugs for treating schizophrenia are postulated to selectively block the D2 dopamine receptor with optimum binding kinetics. The structure of D2 bound to an antipsychotic sheds light on how to design such drugs.

Figure 1 |. Binding sites within crystal structures of D2-like receptors in complex with drug molecules.

Drugs that block the activity of the D2 dopamine receptor (D2R) are used to treat schizophrenia, but also block the closely related D3 and D4 receptors (D3R and D4R), and exhibit debilitating side effects due, in part, to their interactions with other receptors. a, Wang et al. report the crystal structure of D2R in complex with the antipsychotic drug risperidone. They observe structural features and drug–receptor binding interactions not observed in the previously reported structure of D3R with the drug eticlopride (b), or of D4R with nemonapride (c). The drug molecules are shown as coloured space-filling structures, and the regions enclosed by dots make receptor contacts that are unique to each receptor. The identification of these contacts might help receptor-specific binding pockets to be delineated, which would aid the rational design of receptor-selective drugs. Receptors are shown in grey; thick ribbons are α-helices; thin regions are unstructured. EL1 and EL2 are extracellular loops. TMV is a transmembrane-spanning segment.