A 30-year search for better antipsychotic drugs with fewer negative side effects may have taken another step forward thanks to researchers in Chapel Hill.
Antipsychotic drugs are among the most widely prescribed medications for the treatment of schizophrenia, bipolar disorder and autism-spectrum disorders. They usually are accompanied by some pretty awful side effects like weight gain, anxiety, dizziness, severe digestive problems and agitation.
Researchers at UNC-Chapel Hill’s School of Medicine and scientists at UC San Francisco recently published their findings in “Nature” that showed advances in limiting the bad side effects of the antipsychotic drugs while maintaining their effectiveness. They created the first high-resolution map of the dopamine 2 receptor (DRD2) bound to the antipsychotic drug risperidone.
They chose this drug because it is a commonly prescribed FDA approved antipsychotic medication which is used to treat schizophrenia, bipolar disorder and autism spectrum disorder. Risperidone is also one of the very few antipsychotic drugs approved for use by children.
By determining the structure of this drug and the receptor, they hope future drugs can be fine-tuned to better bind with the proper receptors in the brain. Presently, most drugs cannot be designed to target only one type of receptor. They interact with not only DRD2, but also other dopamine, serotonin, histamine and alpha adrenergic receptors, which leads to undesired side effects.
“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,” said UNC researcher Bryan L. Roth, who authored the paper. “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.”
Getting the DRD2 protein to crystalize with a drug bound to it had been impossible for decades because receptors are notoriously fickle proteins - small, fragile and typically in motion as they bind to compounds. But finally Roth and his team that included postdoctoral fellows Sheng Wang and Daniel Wacker, were able to coax DRD2 to crystallize while bound tightly to risperidone. What they discovered was entirely unexpected. They found that the crystal formation created a previously unknown pocket on the receptor. This could allow for new drug molecules to be designed to only bind with the D2 receptor.
“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,” Wacker said. “This is precisely the sort of information we need in order to create safer and more effective therapeutics.”
Typically scientists have solved the chemical structure of proteins using a technique called X-Ray crystallography.
“With this high-resolution structure in hand, we anticipate the discovery of compounds that interact with DRD2 in specific ways important for greater therapeutic actions and fewer side-effects,” Roth said. “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.”