New Opioid Molecule Designed to Prevent Side Effects
Opioids, a category of powerful analgesics, are largely prescribed for the treatment of pain brought on by inflammation and tissue damage, typically associated with nerve damage, surgery, cancer or arthritis.
Usual side effects experienced with opioids are nausea, sedation, physical dependence, vomiting, dizziness, tolerance, constipation, and less commonly, respiratory arrest. Addiction and physical dependence are clinical problems that might hinder correct prescription and satisfactory pain management.
Computational simulation of interactions at opioid receptors
Researchers from Charité-Universitätsmedizin Berlin and the Zuse Institute Berlin have utilized advanced computational simulation to investigate interactions at opioid receptors, which are the docking sites for painkillers in cells; the findings were reported in March 2018, in the journal Science.
Upon being damaged and experiencing pain, tissue becomes inflamed and highly acidic. Its pH is reduced from around 7.4—characteristic of normal, healthy tissue—to between 5 and 7. This indicates an increase in the number of protons moving freely around the injury areas. With this knowledge, the scientists analyzed the effect of the extra protons on the binding characteristics of opioids.
New opioid molecule
The researchers used computer modeling and discovered that the attachment of morphine-like molecules to their μ-opioid receptors was enhanced by the reduction in pH levels. From their innovative discovery, the researchers developed an opioid molecule that could be protonated to be active. They then developed a fluorinated version of the opioid fentanyl molecule, (±)-N-(3-fluoro-1-phenethylpiperidin-4-yl)-N-phenyl propionamide, or NFEPP.
In contrast to the traditional opioid fentanyl, NFEPP exhibited pH-sensitive binding. The inclusion of the fluorine atom attracts electron density from the tertiary amine of the fentanyl, leading to a pKa of 6.8. Therefore, NFEPP gets protonated only in the acidic surroundings of peripheral inflamed or injured tissues.
However, in the brain, where the pH is high, protonation does not occur so NFEPP remains inactive. These findings show that the chemically transformed fentanyl only triggers opioid receptors on pain neurons at the injury site and not in the brain’s normal environment.
Upon being applied to a rat model, NFEPP exhibited pain relief level similar to that of fentanyl in distinctive inflammatory pain types but without exhibiting the related side effects such as constipation, respiratory depression, addiction potential, or sedation.
There was no impact on healthy tissues, indicating that the acute side effects linked to such painkillers can be prevented. Moreover, in contrast to fentanyl, high NFEPP dosage was not found to be hazardous to the rats.
The present findings indicate that the development of drugs that can be activated under specific pathological conditions could be an innovative and advantageous approach for future drug development.
Further experimentation, investigation, and preclinical research are required. The presented data offers unrivaled confidence in the treatment of chronic and postsurgical inflammatory pain without any side effects, which would result in the significant improvement in patients’ quality of life.
- Science, 355:966, 2017
- C&EN, 95:8, 2017
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Last updated: Apr 19, 2018 at 8:22 AM
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