Building on 2 decades of past research, scientists from the Florida campus to The Scripps Research Institute (TSRI) have announced noteworthy progress in the search for a new opioid that delivers the analgesic equivalent of morphine without the major adverse effect of respiratory depression. According to the CDC, some 91 Americans per day die from opioid overdose that slows and then halts the victim’s breathing. Disconnecting the painkilling pathway (G Protein) from the respiratory suppression pathway (beta-arrestin) has been the long-held goal of researchers including current study leader and TSRI professor Laura Bohn, PhD. She commented, with respect to the quest, “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.”
In the current study, Dr. Bohn and colleagues developed over 500 new potential molecules, and isolated more than 60 whose chemical structures displayed degrees of bias between the 2 signaling assays. 6 of these were selected that provided a wide range of bias overall, from preference for barrestin2 recruitment to preference for G protein signaling. These were tested in mouse models to assess analgesic potency and influence on respiration. All were found to provide analgesia equivalent to, or better than, morphine, and those with less bias to barrestin2 were also less likely to provoke respiratory depression. With respect to separating desired effect from side effect, Dr. Bohn concluded “I think what we have done here is shown that bias isn’t all or none—that there is a spectrum.” The findings were reported last week in the journal Cell.
Read a news story about the research.
The journal abstract may be read here.
Posted on November 27, 2017