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Drug Development

An opioid minus major side effects

Fluorinated version of fentanyl is active only in areas of inflammation, eliminating troublesome effects in rats

by Bethany Halford
March 3, 2017 | A version of this story appeared in Volume 95, Issue 10

When given to rats, a new opioid relieves their pain but doesn’t cause the negative side effects typically associated with this class of analgesic, such as addiction, respiratory depression, and constipation (Science 2017, DOI: 10.1126/science.aai8636). “These things are big problems when we treat patients for long periods of time with opioids,” says Christoph Stein, a professor of anesthesiology and critical care medicine at the Free University of Berlin, who led the research.

Stein’s group has spent more than 25 years studying opioid receptors on neurons outside the brain and spinal cord. These receptors, he says, become more active at sites of injury or inflammation. Knowing that pH is lower at such sites and that therefore more protons are floating around, Stein teamed up with Marcus Weber at Zuse Institute Berlin to computationally model what the extra protons might be doing to the binding behavior of opioids. They found that the lower pH greatly improved the opioids’ binding.

“We then asked the question, Can you make a compound that acts only in the inflamed environment and not in the normal environment in the brain,” where many side effects originate? Stein explains. They settled on a fluorinated version of fentanyl called NFEPP. The addition of a fluorine atom draws electron density from the compound’s tertiary amine, which must be protonated for the compound to be active. NFEPP has a pKa of 6.8, so it’s protonated only in the low-pH environment of injured or inflamed tissue. In the brain, however, NFEPP isn’t protonated and is therefore inactive, Stein says.

Grégory Scherrer, who studies opioids and molecular mechanisms of pain at Stanford University, wonders about NFEPP’s mechanism of action. Stein’s team provides evidence that the compound acts predominantly on opioid receptors present on pain neurons at the site of injury, he points out. But they don’t show how NFEPP modifies the function of those pain neurons. Does it reduce excitability of cells that signal pain to the brain? If so, what ion channels are involved? he asks, adding, “I’m excited to follow the authors’ future work and to have answers to these questions.”



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