New Painkillers Reduce Overdose Risk
Left to right: Study first author Cullen Schmid, staff scientist, and TSRI Professor Laura Bohn (Photo courtesy Laura Bohn)
JUPITER, Fla. Nov. 16, 2017 Scientists on the Florida campus of The Scripps Research Institute (TSRI) have developed new opioid pain relievers that reduce pain on par with morphine but do not slow or stop breathing the cause of opiate overdose.
The research, published today in the journal Cell, describes a method for making safer opioid painkillers. According to the U.S. Centers for Disease Control and Prevention, 91 Americans die every day from opioid overdoses deaths caused when opiates like oxycontin, heroin and fentanyl slow and eventually stop a person's breathing.
Study leader TSRI Professor Laura M. Bohn, Ph.D., said the research shows that a range of compounds can deliver pain-blocking potency without affecting respiration.
The study builds on two decades of research by Bohn and her colleagues, who long questioned whether the painkilling pathway, called the G protein pathway, could be unlinked from the breathing suppression pathway, called the beta-arrestin pathway.
One of the questions we had was how good we can get at separating out the pathways, and how much separation do we need to see analgesia without respiratory suppression, Bohn said.
For the study, the Bohn worked closely with TSRI chemist Thomas Bannister, Ph.D, to develope new potential drug molecules; they then tweaked their chemical structures to systematically vary the bias between the two pathways G protein signaling and beta-arrestin recruitment. The group developed more than 500 compounds in the past six years, and they found more than 60 that showed bias between signaling assays. They then selected six compounds to represent a wide range in the degree of bias (from those that preferred barrestin2 recruitment to those that almost exclusively preferred G protein signaling) and determined their overall potency for inducing analgesia and respiratory suppression in mouse models.
The researchers found that the new compounds could indeed enter the brain and all of the compounds were as potent, if not more so, than morphine. The compounds that were less able to promote barrestin2 associations in cells were also less likely to induce respiratory suppression in mice.
In contrast, the painkiller fentanyl was shown to prefer receptor-barrestin2 associations and also had a more narrow safety margin. In short, the fentanyl dose needed to alleviate the perception of pain was closer to the dose that suppressed breathing, which may be why fentanyl is more likely to trigger respiratory suppression at low doses. Fentanyl is a powerful pain killer, but one with a narrow therapeutic window and a history of overdoses. While this issue requires more research, this at least brings into question whether this may be part of the reason, Bohn said.
Bohn explained that separating the receptors ability to engage in the two pathways can provide a way to separate desired drug effects from side effects.
I think what we have done here is shown that bias isn't all or none that there is a spectrum. That suggests an opportunity to expand the therapeutic window, or the range of doses at which a drug may be administered safely, she said.
The results announced today are the culmination of nearly six years of work by TSRI scientists including Cullen Schmid, Ph.D., Nicole Kennedy, Ph.D., and Michael Cameron, Ph.D.; as well as former members of the research lab: Jenny Morgenweck, Ph.D., Zhizhou Yue, Ph.D., Kim Lovell, Ph.D. and Nicolette Ross, Ph.D. The work was funded by the National Institute on Drug Abuse of the National Institutes of Health (grants R01 DA033073 and R01 DA038694).
About The Scripps Research Institute
The Scripps Research Institute (TSRI) is one of the worlds largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists including two Nobel laureates and 20 members of the National Academies of Science, Engineering or Medicine work toward their next discoveries. The institutes graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. In October 2016, TSRI announced a strategic affiliation with the California Institute for Biomedical Research (Calibr), representing a renewed commitment to the discovery and development of new medicines to address unmet medical needs. For more information, see www.scripps.edu.
# # #
For information:
Office of Communications
Tel: 858-784-2666
Fax: 858-784-8118
press@scripps.edu
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New Painkillers Reduce Overdose Risk 
