In Search of Safer Synthetic Opioids

Aug 02 2017

In Search of Safer Synthetic Opioids

One of the major drivers of the U.S. opiate epidemic has been abuse of fentanyl and fentanyl-like substances, man-made synthetic opioids that are 100 times stronger than morphine and 40 to 50 times more potent than heroin. A single dose of fentanyl can cause death within minutes by paralyzing chest muscles and preventing breathing.

But researchers in Germany may have found a way to make fentanyl safer by altering its molecular structure, and targeting its effects.

Using computer modeling, a team led by Christoph Stein, Charité – Freie Universität Berlin, and Marcus Weber, Zuse Institute Berlin, modified the chemical structure of fentanyl to create a new opioid, named NFEPP, that only binds to mu-opioid receptors (MORs) under the acidic conditions that occur in inflammation.

Doing so enabled the researchers to direct NFEPP’s effects only to areas where inflammation exists, caused by tissue injury. In two laboratory rat models of inflammatory pain, NFEPP reduced pain but did not lead to typical side effects such as sedation, addiction, and respiratory depression.

Researchers believe those and other side effects happen because existing synthetic opioids act upon MORs located throughout the body and brain, without distinguishing between healthy and unhealthy areas. So, they have explored strategies to make opioids more specific to pain pathways without affecting non-pain pathways, by targeting only certain opioid receptors.

Stein found one unique property of damaged tissue that could be exploited to target opioids to specific sites. One such property is inflammation, which causes a drop in pH from physiological levels of 7.4 to acidic levels of about 5.4.

Co-first authors Viola Spahn and Giovanna Del Vecchio, along with Stein and colleagues, theorized that an opioid that binds MORs only during acidic conditions should activate the receptors only at sites of injury, where pain signals originate.

“There are several indications that MORs can be pH sensitive,” Stein says. “So Marcus Weber’s team created an artificial inflamed environment in a computer simulation to explore how changes in pH could affect MOR signaling and agonist binding,” he says. “The biggest advantage with this is that we may be able to avoid side effects seen with opioids and even NSAIDs, which can cause other serious problems like gastric ulcers, cardiovascular issues, and stroke,” Stein adds.

Michael Bruchas, Washington University, St. Louis, US, who was not involved in the study, called it “a very exciting development that you could have a mu-opioid receptor agonist that would be more preferential to the site of injury. People have been working on biased opioid agonists that are tuned to one pathway over another, but this is a different angle in that it was designed as a pH-sensitive molecule,” he told Pain Research Forum.

Future research on NFEPP will include studying whether the same approach could be applied to improve other recently developed, synthetic opiates. “If you could combine this process with other methods of biasing downstream opioid signaling pathways, you could really produce a very robust, safer opioid analgesic,” Bruchas says.

NFEPP won’t be available for general use anytime soon. Stein says the next step will be Good Manufacturing Practice [GMP] production of the compound to test it in human trials, “but that is a very expensive process.”

The study was published earlier this year by Science magazine.

The use of synthetic opioids has increased rapidly because they are often inexpensive to buy. The key ingredient for fentanyl can be obtained cheaply from sources overseas, where it is unregulated.

Dealers often combine synthetics to create new drugs, or press them into pills to be sold as prescription painkillers such as Oxycontin or Norco. Fentanyl has also been blended into the anti-anxiety drug Xanax.