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Drug Development

Cyclic peptide could provide pain relief without causing euphoria

In mice, the molecule relieves drug-seeking behavior and dampens stress response

by Megha Satyanarayana
April 1, 2019

In the 1980s, pharmaceutical companies tried to build opioid painkillers that wouldn’t lead to addiction by taking advantage of an interesting phenomenon that happens when targeting the kappa opioid receptor in the brain. Compounds that activate this receptor cause both pleasant side-effects, like euphoria, and less pleasant ones, like depression. The hope in targeting this receptor was that the less pleasant side effects would quell the pleasant ones that often led to misuse.

But there was a catch, said Charles Chavkin, an opioid pharmacologist at the University of Washington.

“It turned out that patients would take them only one time, and yes, they’d produce analgesia, but they would make them feel lousy,” he said, describing the results of early trials of the compounds. Pharma all but abandoned developing kappa opioid receptor drugs soon after.

Some 30 years later, scientists are still searching for an opioid that doesn’t lead to addiction. University of Florida researchers Jane Aldrich and Jay McLaughlin think they may have an answer—a tiny cyclic peptide called JVA4001. The molecule seems to both activate and suppress the kappa opioid receptor, potentially by binding to different places in the protein. In a presentation on Monday at the American Chemical Society national meeting in Orlando, in the Division of Medicinal Chemistry, Aldrich said that this macrocyclic peptide, with picomolar activity in the brain, means scientists are getting closer to a painkiller that doesn’t also trigger the kind of intense euphoria that leads to addictive behavior.

“It’s one of the most exciting compounds I’ve looked at in my career,” she said, based on experiments in mice that test pain and drug-seeking behavior.

To develop the peptide, Aldrich and her team looked to a natural cyclic peptide derived from the fermentation of woodchips called CJ-15,208. That compound had already been described by other researchers as being able to both activate and suppress the kappa opioid receptor. Such circular proteins are interesting drug scaffolds because they can potentially survive the various enzymes in the stomach, gut, and blood stream that chew up proteins end-to-end. In addition, Aldrich said, some macrocyclic peptides can cross the blood brain barrier, a critical hurdle in creating a neuroactive drug.

A structure of a circular peptide that provides pain relief without euphoria
Credit: Jane Aldrich, University of Florida

Aldrich and colleagues took CJ-15,208 and substituted different amino acids in the peptide to develop something that had fewer side effects. The result was JVA4001.

This compound seems to block mice’s desire for cocaine, ethanol, and morphine in a test that mimics drug-seeking behavior, she said, while at the same time, the animals treated with the compound can withstand more of a painful stimulus, such as placing their tails in warm water, compared with untreated mice.

Chavkin thinks a cyclic peptide could be just as likely to solve the pain relief without euphoria problem as a conventional small molecule. Nevertheless, he said, Aldrich’s effort to make a safe, analgesic medicinal peptide is important.

Aldrich said their next steps are to refine the pharmacokinetics of the compound. And she pointed to an interesting phenomenon that she thinks might make JVA4001 and related peptides successful in fighting pain without promoting addiction. One of the major causes for people with substance abuse problems to relapse is stress. In mouse experiments, JVA4001 seemed to dampen the animals’ stress response, leading them to not look for the drug they once took to feel so good.



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