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Discovery of DRD2 structure bound to risperidone could lead to improved antipsychotics
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Researchers have discovered the first high-resolution crystal structure of the dopamine 2 receptor, or DRD2, bound to risperidone, which will enable scientists to activate only this receptor thus potentially curbing common adverse effects and creating safer therapeutics, according to a press release.
"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," Bryan L. Roth, MD, PhD, the Michael Hooker Distinguished Professor of Protein Therapeutics and Translational Proteomics at the UNC School of Medicine, said in a press release. "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."
Many antipsychotic drugs, including atypical risperidone, primarily target the DRD2 and usually cause serious adverse effects, according to Roth and colleagues. Therefore, understanding the DRD2 structure at the molecular level, as well as its function, could provide a way to create safer, more effective treatments for schizophrenia, bipolar disorder and other psychiatric illnesses. Until this discovery, researchers did not have access to a high-resolution crystal structure of DRD2 attached to a compound, making it difficult to directly target the correct receptor, according to the researchers.
Roth and colleagues conducted a series of structural studies over several years using an engineered human DRD2 construct to crystalize DRD2 while bound to risperidone. With the high-resolution image and further computational modeling, they found that risperidone binds to DRD2 unpredictably, with a previously unseen pocket on the receptor which the researchers believe could be targeted to create more effective therapeutics, according to the report. Furthermore, with the structure of risperidone bound to DRD2 uncovered, common side effects of antipsychotic drugs may be avoided in the future.
“Our lack of knowledge into how antipsychotic drugs bind to their receptors has held back progress towards creating more effective medications,” Roth said in the release. “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. 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.” – by Savannah Demko
Disclosures: The authors report no relevant financial disclosures.
Perspective
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Joshua L. Roffman, MD, MMSc
Schizophrenia and other psychotic illnesses are among the most dramatic, debilitating and costly of mental health problems. All antipsychotic medications — including both first-generation (eg, haloperidol, chlorpromazine) and second-generation (eg, risperidone, olanzapine) drugs — block the dopamine D2 receptor, which is thought to be critical to their efficacy. However, antipsychotic medications are also promiscuous with regard to activity at other receptor subtypes, which likely contributes to their manifold adverse effects.
In this context, a better understanding of how antipsychotic medications interact with D2 and other classes of dopamine receptors could potentially lead to development of improved and more specific classes of antipsychotic medications. With the crystal structure of the D2 receptor now resolved by Wang and colleagues, there is a new opportunity for progress along these lines.
It is important to recognize, though, that even this elegant, high resolution view of the D2 receptor may not be sufficient to develop cleaner or more efficacious drugs for treating psychosis. With regard to adverse treatment effects, while antipsychotic medications (especially first-generation drugs) can cause extrapyramidal symptoms and other movement disorders, there is no evidence that these effects are mediated through their effects at other dopamine receptor subtypes. Rather, the core issue here appears to be that systemic administration of D2 blocking medications impacts multiple dopaminergic projections — that is to say, they block signaling not only within mesocortical and mesolimbic pathways (resulting in a reduction in psychosis), but also in nigrostriatal and tuberoinfundibular pathways (resulting in extrapyramidal symptoms and prolactin-related abnormalities). By the same token, more specific D2 antagonism may result in improved efficacy and in more pronounced motoric side effects.
That said, in current clinical practice, metabolic syndromes (weight gain, diabetes and related cardiovascular disease) associated with second-generation antipsychotic drugs pose a much graver threat to life and health than do off-target D2 effects. In conjunction with smoking, poorer access to medical care, and other related factors, chronic use of these medications in patients with schizophrenia may reduce their lifespan by two decades or more. Again, it is likely that these effects reflect activity of antipsychotic drugs at receptors other than dopamine (eg, serotonin 5HT2c, muscarinic M3).
It is also important to recognize that schizophrenia is a biologically complex disorder that clearly involves other neurochemical abnormalities than in dopamine signaling. While generally effective against the positive symptoms of schizophrenia (hallucinations, paranoid delusions), antipsychotic medications do not improve negative symptoms (apathy, lack of motivation, affective flattening) and related impairment in cognition; unfortunately, these symptoms cause substantially greater functional deficits than do positive symptoms. Arguably the best chance for developing improved treatments for psychosis lies with achieving a more comprehensive understanding of its diverse biological underpinnings.
References:
Laursen TM, et al. Curr Opin Psychiatry. 2012;doi:10.1097/YCO.0b013e32835035ca.
Reynolds GP, Kirk SL. Pharmacol Ther. 2010;doi:10.1016/j.pharmthera.2009.10.010.
Shamsi S, et al. Schizophr Res. 2011;doi:10.1016/j.schres.2010.08.007.
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