Structural Model of DRD2 Could Lead to Better Antipsychotic Medication

A model recently created at the University of North Carolina (UNC) School of Medicine using X-ray crystallography shows an indentation on the receptor DRD2, which may allow scientists to develop more selective antipsychotic medication with fewer side effects. This could prevent such symptoms as “weight gain, anxiety, dizziness, severe digestive problems, agitation, and many others” (UNC Health Care, 2018).

Bryan Roth, MD, PhD, is the Michael Hooker Distinguished Professor of Protein Therapeutics and Translational Proteomics at the UNC School of Medicine. Dr. Roth used to specialize in treating patients with schizophrenia. He noted that the “medications were only modestly effective for large numbers of patients. Our lack of knowledge into how antipsychotic drugs bind to their receptors has held back progress towards creating more effective medications. Solving the high-resolution crystal structure of DRD2 bound to the commonly prescribed antipsychotic drug risperidone is the first step towards the creation of safer and more effective medications for schizophrenia and related disorders” (UNC Health Care, 2018).

Risperidone, a “commonly prescribed antipsychotic medication which is FDA-approved for use for schizophrenia, bipolar disorder, and autism spectrum disorder” (UNC Health Care, 2018) was bonded with the DRD2 receptor. This experiment revealed that its “binding mode was unpredictable–there was a previously unseen pocket on the receptor which Roth and colleagues think could be targeted to create more selective medications” (UNC Health Care, 2018).

Before this breakthrough, scientists were unable to “target only one type of receptor” and pharmaceuticals would “interact with not only DRD2, but a myriad of other dopamine, serotonin, histamine, and alpha adrenergic receptors, leading to serious side effects” (UNC Health Care, 2018). Daniel Wacker, PhD, the co-corresponding author of the study, states, “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. This is precisely the sort of information we need in order to create safer and more effective therapeutics” (UNC Health Care, 2018).