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Designer agent blocks pain in mice without morphine's side effects

Structure-based molecule selectively targets brain analgesic circuitry -- NIH-funded study

NIH/National Institute of Mental Health

Scientists have synthesized a molecule with a unique profile of highly specific pain-relieving properties and demonstrated its efficacy in mice. Compared to existing opioid pain relievers, like morphine, the new agent, called PZM21, was not "reinforcing" or prone to triggering potentially lethal respiratory impairment - and was also less constipating. Also unlike existing analgesics, it had little effect on spinal cord reflexive responses, instead targeting the brain-mediated emotional/experiential component of pain. In addition to clinical potential, PZM21 also holds promise as a "tool molecule" for exploring the workings of brain pain systems, say the researchers.

The study represents the combined efforts of NIH-funded research teams led by Nobel laureate Brian Kobilka, M.D., of Stanford University, Bryan Roth, M.D., Ph.D., of the University of North Carolina, and Brian Shoichet, Ph.D., of the University of California San Francisco. They report on their findings August 17, 2016 in the journal Nature.

They achieved PZM21's specificity by applying knowledge of opioid receptor structure to design an agent optimized for just the desired properties. Evidence suggested that the undesirable side effects of morphine-like opiates work on the receptor through a molecular signaling pathway linked to beta-arrestin, while the desired analgesic effects work through a G protein-coupled receptor pathway. The researchers screened and ranked more than 3 million compounds for these properties - evaluating each in about 1.3 million configurations for their ability to tweak the opioid receptor in the desired ways. After exhaustive winnowing, they used the knowledge gained to synthesize the strongest G protein and weakest beta-arrestin activator. PZM21's unprecedented chemical structure then performed just as they had theorized in mouse tests of analgesic and side effect potential.

"This work demonstrates the power of structure-based design to speed up the development of drugs with optimal signaling and therapeutic properties" explained Laurie Nadler, Ph.D., chief of the Neuropharmacology Program of the NIH's National Institute of Mental Health, which co-funded the research along with NIH's National Institute of General Medical Sciences and National Institute on Drug Abuse.

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ARTICLE: Manglik A, Lin H, Aryal DK, McCorvy JD, Dengler D, Corder G Levit A, Kling RC, Bernat V, Hubner H, Huang X-P, Sassano MF, Giguere PM, Lober S, Duan D, Scherrer G, Kobilka BK, Gmeiner P, Roth BL, Shoichet BK. Structure-based discovery of opioid analgesics with reduced side effects. Nature, Aug. 17, 2016. DOI: 10.1038/nature19112.

About the National Institute of Mental Health (NIMH): The mission of the (NIMH) is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure. For more information, visit the NIMH website http://www.nimh.nih.gov.

About the National Institute on Drug Abuse (NIDA): The National Institute on Drug Abuse (NIDA) is a component of the National Institutes of Health, U.S. Department of Health and Human Services. NIDA supports most of the world's research on the health aspects of drug use and addiction. The Institute carries out a large variety of programs to inform policy, improve practice, and advance addiction science. Fact sheets on the health effects of drugs and information on NIDA research and other activities can be found at http://www.drugabuse.gov.

NIGMS is a part of NIH that supports basic research to increase our understanding of life processes and lay the foundation for advances in disease diagnosis, treatment and prevention. For more information on the Institute's research and training programs, see http://www.nigms.nih.gov.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit the http://www.nih.gov.

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