Although antipsychotic medications have helped many people with schizophrenia, bipolar disorder, and autism-spectrum disorders, the drugs often come with severe side effects due to their interactions with dozens of other brain receptors.
In a new study, researchers at the University of North Carolina (UNC) School of Medicine and the University of California, San Francisco (UCSF) have solved the first high-resolution crystal structure of the dopamine 2 receptor (DRD2) bound to the antipsychotic drug risperidone, resulting in a long-awaited tool for drug developers, psychiatrists, and neuroscientists.
The finding will allow scientists to selectively activate DRD2, thus potentially reducing a large number of serious antipsychotic drug side effects such as weight gain, anxiety, dizziness, severe digestive problems, agitation, involuntary muscle movement, and many others.
“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 senior author Bryan L. Roth, M.D., Ph.D., 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.”
Around 30 percent of the drugs on the market activate G-protein coupled receptors on cell surfaces and trigger chemical signals inside cells to produce their therapeutic effects.
For antipsychotic medications, one effect is alleviating psychotic symptoms associated with schizophrenia, bipolar disorder, and many other psychiatric diseases.
Unfortunately, since scientists haven’t understood the structural differences between the many different kinds of receptors in the brain, most drugs cannot be developed to target only one type of receptor. Instead, they interact with not only DRD2, but a myriad of other dopamine, serotonin, histamine, and alpha adrenergic receptors, leading to serious side effects.
For 30 years, DRD2 has undergone extensive study, but until now researchers lacked a high-resolution structure of DRD2 attached to a compound. Risperidone is a commonly prescribed antipsychotic medication approved for use in schizophrenia, bipolar disorder, and autism spectrum disorder. Risperidone is also one of the very few ‘atypical’ antipsychotic drugs approved for use in children.
“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.
Researchers have traditionally studied the chemical structure of proteins using a technique called X-Ray crystallography. They use various methods to induce the protein to condense into a tightly packed crystal lattice, then shoot x-rays at the crystal, and finally calculate the protein’s structure from the resulting diffraction patterns.
However, getting the DRD2 protein to crystalize while also bound to a drug has been impossible for decades because receptors are notoriously fickle proteins — small, fragile, and typically in motion as they bind to compounds.
To overcome the technical challenges, the research team conducted a series of painstaking studies over several years to coax DRD2 to crystalize while bound tightly to risperidone.
Once they had the high-resolution image, they were able to see that risperidone binds to DRD2 in an entirely unexpected way. Further computational modeling performed by UCSF researchers showed that risperidone’s binding mode was unpredictable. They discovered a previously unseen pocket on the receptor which could be targeted to create more selective 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.” said Daniel Wacker, Ph.D., co-corresponding author of the study. “This is precisely the sort of information we need in order to create safer and more effective therapeutics.”
The new findings are published in the journal Nature.