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Discovery by Jin, Roth Could Lead to Better Schizophrenia Drugs

Scientists led by researchers at the UNC Eshelman School of Pharmacy have discovered three first-in-class chemical compounds that could lead to safer, more effective medications for schizophrenia and related disorders.

Schizophrenia is typically treated with antipsychotic medications, but the medications do not adequately treat a high percentage of patients. The drugs don’t address the negative and cognitive symptoms of schizophrenia, and all current antipsychotics can lead to serious side effects such as cardiovascular conditions and weight gain with chronic use.

The new compounds, which UNC has patented, will help address these problems by enabling researchers to better study which key signaling pathways in the body are essential to the effectiveness and side effects of antipsychotics, says Jian Jin, PhD, one of the study’s corresponding authors and the associate director of medicinal chemistry at the pharmacy school’s Center of Integrative Chemical Biology and Drug Discovery.

“These compounds are unprecedented,” says Jin, who spearheaded the medicinal chemistry portion of the research. “They give biomedical researchers a powerful tool for studying the relationship between signaling pathways and the efficacy and side effects of antipsychotic medications. That understanding will help us design better treatments. “At the same time, these novel compounds themselves could be developed into clinical candidates for treating schizophrenia and related disorders, with improved efficacy and fewer side effects. So this discovery is highly significant.”

The study’s findings are described in a paper to be published during the week of October 24 in the online Early Edition for the journal Proceedings of the National Academy of Sciences, USA. Jin and Bryan Roth, PhD, MD, led a team that included researchers from Duke University and Columbia University. Roth, who directed the pharmacological component of the study, is a Michael Hooker Distinguished Professor in the UNC School of Medicine and the pharmacy school.

There are two major types of signaling pathways for this drug target. One type is mediated by a class of proteins called G proteins, while the other is controlled by a different group of proteins, including a prominent one called beta-arrestin. The new compounds activate the beta-arrestin pathways but not the G protein-mediated pathways, allowing researchers to study them separately.

“This discovery provides a completely new approach for treating schizophrenia and related disorders with greater efficacy and fewer side effects,” says Roth, who directs the National Institute of Mental Health Psychoactive Drug Screening Program at UNC-Chapel Hill.

Jin and Roth are also working to identify compounds that would activate only the G protein-mediated pathways. Jin said that only a very limited number of functionally selective compounds — compounds that selectively activate one signaling pathway over the other — have been reported to date.

“Prior to our study, there had been very little purposeful attention devoted to creating and annotating novel compounds that show functional selectivity,” Jin says. “Our approach, which combines comprehensive medicinal chemistry and pharmacological profiling, provides a successful proof-of-concept for how such compounds can be discovered and validated.”

The study was supported by funding from the National Institutes of Health and the NIMH. The co-first authors are John A. Allen, PhD, and Vincent Setola, PhD, from Roth’s lab and Julianne M. Yost, PhD, from Jin’s lab. Other researchers who worked on the project include

  • From Roth’s lab: Maria F. Sassano, PhD; Prem N. Yadav, PhD; Xi-ping Huang, PhD; and Niels H. Jensen, PhD
  • From Jin’s lab: Xin Chen, PhD
  • From the CICBDD: center director Stephen V. Frye, PhD
  • From the Duke University Medical Center: James B. Duke Professor Marc G. Caron, PhD; associate professor William C. Wetsel, PhD; Meng Chen, PhD; and Sean Peterson
  • From the College of Physicians and Surgeons at Columbia University: professor Jonathan A. Javitch, MD, PhD; and Bo Feng, PhD
  • From the Center for Combinatorial Chemistry and Drug Discovery at Jilin University in China: professor Xu Bai, PhD, and Xin Che, PhD