Opioids relieve pain, but they also produce life-threatening side effects. Respiratory depression, the slowing of breathing, is one of them and the leading cause of death from opioid overdose. To make safer opioids, scientists have explored a unique strategy called “biased agonism” where modifications to an opioid’s chemical structure allow the drug to relieve pain but avoid unwanted consequences.
Now, new research uncovers important details about biased agonism that may make it an even more effective strategy. Led by Laura Bohn at the Scripps Research Institute in Juniper, Florida, a team of biologists and chemists identify key structural features of opioids that can enhance biased agonism. With this information, they generate a series of new opioids that, in mice, relieve pain just as well as morphine but have minimal effects on breathing.
“I love reading stuff like this,” says William Schmidt, NorthStar Consulting, Davis, California, an expert on drug development who was not involved in the study. “These compounds clearly cause much less respiratory depression than other opioid-related compounds while still producing strong pain relief.”
The study was published online November 16, 2017, in the journal Cell.
Heading towards pain relief and away from respiratory depression
Opioids produce pain relief, and side effects too, by attaching to and activating opioid receptors, which are proteins that sit on the surface of cells. When turned on, the receptors initiate multiple cascades of molecular signals, known as signaling pathways, inside the cell.
Nearly fifteen years ago, Bohn found that when an opioid attaches to a mu opioid receptor (one of four types of opioid receptors, with the acronym MOR), this activates two signaling pathways: one that relieves pain, and another that suppresses breathing and causes other side effects. Activating a receptor to result in a biological response within the cell is called agonism, and the drugs that do so are called agonists.
When agonists such as morphine or fentanyl bind to and activate the MOR, both the pain relief pathway, and the pathway that leads to side effects, come into play, more-or-less equally.
This laid the groundwork for a new strategy called biased agonism: the idea that researchers could make an opioid safer if it was “biased” to recruit into action only the pain relief pathway, and leave the respiratory depression pathway untouched. In this context, the extent of bias toward the pain relief pathway is considered an agonist’s “bias factor.”
Last year, the biopharmaceutical company Trevena brought this strategy to people in a late-phase clinical trial using their own MOR biased agonist, called TRV130. Although it relieved pain just as well as morphine, this drug only avoided respiratory depression at doses that were not high enough to relieve pain. It turned out that TRV130 only had a bias factor of three, meaning it drove the pain relief pathway 3 times as much as the pathway that produces side effects.
So Bohn and her colleagues wondered: could an opioid with a higher bias factor better avoid respiratory depression but still relieve pain?
Bohn and her team answered this question by identifying changes to the structure of MOR agonists that enhanced the bias factor. They designed five slightly different compounds with bias factors ranging from 11 to 85—an order of magnitude higher than that of Trevena’s TRV130.
“They show the highest degree of biased agonism in this group of drugs I’ve seen,” remarked Schmidt.
The team then tested each compound’s effect on pain sensitivity and breathing in mice. They found that the drugs reduced sensitivity to painful heat (a common way to assess the effects of pain relievers in animals) just as much as morphine. But, unlike morphine, the compounds had minimal effects on breathing.
Further, the higher the bias factor, the less of an effect each compound had on breathing. This validates the idea that the presence of bias alone is not enough. Instead, the extent of bias is important too.
The new study, then, puts the clinical trial results from Trevena’s biased agonist in a different light. It suggests that the company’s TRV130, with its bias factor of three, simply may not have been biased enough to avoid detrimental effects on breathing while maintaining pain relief. The current research leaves hope that biased agonism could still be an effective approach for future drug development.
“This is a tremendous win, because it demonstrates an important concept in the field while also pointing toward some new compounds for therapeutic development,” remarked Schmidt.
Although promising, further research is needed to confirm these highly biased agonists don’t just relieve experimental heat pain, but also other forms of acute or chronic pain. Whether increasing the bias factor will create safer drugs that alleviate pain in people too also awaits further study.
To read about the research in more detail, see the related Pain Research Forum news story here.
Nathan Fried is a postdoctoral fellow at the University of Pennsylvania, Philadelphia, US.