An opioid minus major side effects | March 6, 2017 Issue - Vol. 95 Issue 10 | Chemical & Engineering News
Volume 95 Issue 10 | p. 8 | News of The Week
Issue Date: March 6, 2017 | Web Date: March 3, 2017

An opioid minus major side effects

Fluorinated version of fentanyl is active only in areas of inflammation, eliminating troublesome effects in rats
Department: Science & Technology
News Channels: Biological SCENE, Organic SCENE
Keywords: pharmaceuticals, opioid, NFEPP, fentanyl

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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Comments (March 3, 2017 3:08 PM)
I want to be a test subject!
Dr Philip Neil Edwards (March 9, 2017 11:02 AM)
A protonated amine with pKa 6.8 (assumed thermodynamic and therefore at 25C and zero ionic strength) will have a pKa at 37C approximately 0.2 units lower - i.e. 6.6.
Inflamed tissues typically have increased perfusion of both blood and lymph which reduces excess production and accumulation of lactic acid and related species and reduces the pH difference between such tissues and those in non-inflamed brain. Overall it is very unlikely that the percentage of protonated extracellular drug will differ by much more than a factor of two between these differing environments - perhaps 30% vs ~15% protonated (intracellular differences will be much smaller).
Dr. William H. Streng (March 11, 2017 1:08 PM)
I read with interest the above in my C&EN. I have a question for Prof. Stein regarding its lack of activity in the brain. Do you know if it is in fact crossing the blood brain barrier to any appreciable extent? When a compound is modified by the introduction of a fluorine atom,there is usually a reduction in the solubility. IF the pKa is 6.8 then 50% of the compound will be protonated at pH 6.8 and if the pH is 7.8 then 10% of the compound will be protonated. Even though 10% is a relatively small amount it would present a driving force to interact within the brain. I do not have any information with me regarding the pH in the brain but I do not believe it is above 7.8. Compounds are known which have biological activity but do not cross the blood brain barrier. An example is the first non-sedating antihistamine. If it entered the brain it would have activity in the brain but because it does not it does not cause someone to become sleepy. I am encouraged by the results of the above work and look forward to hearing more about this.

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