Dopamine Receptor–Drug Structure Could Aid Development of Safer Antipsychotics

Illustration of the dopamine 2 receptor bound to the antipsychotic drug risperidone. [Roth Lab/UNC School of Medicine]

Scientists at the University of North Carolina (UNC) at Chapel Hill have resolved the structure of the D₂ dopamine receptor (DRD2) bound to the antipsychotic drug risperidone. The researchers, led by Bryan L. Roth, M.D., Ph.D., hope that the new insights provided by the structure—which included some surprises—will help in the design of safer drugs for psychiatric disorders, including schizophrenia and bipolar disorder, and autism-spectrum disorders.

“If we want to create better medications, the first step is to see what the D₂ receptor looks like in high-resolution detail when it's bound tightly to a drug,” comments Prof. Roth, who is the Michael Hooker Distinguished Professor of Protein Therapeutics and Translational Proteomics at the UNC School of Medicine. “We now have the structure, and we're exploring it to find new compounds we hope can help the millions of people in need of better treatments.” The team reports their results in Nature, in a paper entitled “Structure of the D₂ Dopamine Receptor Bound to the Atypical Antipsychotic Drug Risperidone.”

The actions of the neurotransmitter dopamine are mediated by a family of five G-protein-coupled receptors (GPCRs), designated D₁ through to D₅. Of these, DRD2 is the primary target for both typical and atypical antipsychotic drugs as well as for Parkinson’s disease drugs, the authors explain. Unfortunately, drugs that target DRD2 may also interact with other receptors for dopamine, as well as with serotonin, histamine, and alpha-adrenergic receptors, and this can cause potentially life-threatening side effects.

The DRD2 receptor was first cloned nearly 30 years ago and has since been the subject of intense study. However, while the high-resolution structures of the related D₃ and D₄ dopamine receptors complexed with ligands have previously been reported, scientists haven’t yet resolved the structure of the DRD2 receptor bound to a drug ligand, “impeding a molecular understanding of the receptor’s function,” the authors write.

The UNC team spent years fine-tuning the techniques, reported in the Nature paper, which would allow them to successfully resolve the crystal stucure of DRD2 bound with the atypical antipsychotic drug risperidone, which is approved for treating schizophrenia, bipolar disorder, and autism-spectrum disorder.

They report that the receptor–drug complex includes some suprising aspects to risperidone binding, which could help to direct future design of drugs that target DRD2. “The DRD2–risperidone structure reveals an unexpected mode of antipsychotic drug binding to dopamine receptors, and illuminates structural determinants essential for the actions of risperidone and related drugs at DRD2,” the authors write.

Comparing the overall ligand binding pocket of DRD2 with those of ligand-bound DRD3 and DRD4 revealed what the authors called “striking differences.” In particular, computational modeling by the UNC team’s collaborators at the University of California, San Francisco, found that risperidone’s binding was unpredictable and that the DRD2 receptor structure contains a previously unidentified pocket that could potentially represent a highly selective target for new drugs.

“Now that we can see the structural differences between similar receptors, such as the dopamine D₄ receptor and DRD2, we can envision new methods for creating compounds that only bind to DRD2 without interacting with dozens of other brain receptors,” suggests corresponding author Daniel Wacker, Ph.D. “This is precisely the sort of information we need in order to create safer and more effective therapeutics.”

The findings may also help to explain how to design new drug compounds that are less likely to cause adverse effects, such as extrapyramidal symptoms. “Now that we’ve solved the structure of risperidone bound to DRD2, we are getting an idea how these side effects could be avoided,” comments co-author Sheng Wang, Ph.D. “Solving the high-resolution crystal structure of DRD2 bound to the commonly prescribed antipsychotic drug risperidone is the first step toward the creation of safer and more effective medications for schizophrenia and related disorders,” Prof. Roth concludes.