An opioid drug with a low risk of addiction and respiratory depression has emerged as a promising candidate for treating chronic pain and pruritus, a condition that compels people to scratch their skin. And it's already on the market.
Researchers from the Hefei Institute of Physical Science of the Chinese Academy of Sciences (CAS) and the Shanghai Institute of Materia Medica, CAS, have developed a kappa opioid receptor (KOR) biased agonist using difelikefalin, a Food and Drug Administration (FDA)-approved peptide that treats severe itching in patients with chronic kidney disease undergoing dialysis.
Difelikefalin doesn't target the mu opioid receptor, as morphine and oxycodone do. Instead, it activates the kappa opioid receptor (KOR) to relieve pain and itching. However, the current medications that affect the KOR come with some debilitating side effects, including sedation, anxiety, and dizziness.
In this study, the scientists took the existing difelikefalin and made a very small structural modification to create an experimental analogue from it, known as beta01. This tweaked compound was then administered to mice.
When a drug activates the KOR, it can trigger multiple signaling pathways inside a cell. The main pathway involves G proteins, which are thought to be responsible for the drug's positive effects, such as relieving pain and itching. Another pathway involves a protein called β-arrestin, which helps regulate the receptor after it's activated.
It's thought that while G-protein signaling causes the drug's beneficial effects, β-arrestin signaling triggers the undesirable ones.
So the researchers redesigned difelikefalin to activate the G-protein pathway while steering clear of β-arrestin.
In an itch model, the drug almost completely prevented scratching caused by chloroquine. It also proved effective in a pain model using acetic acid-induced writhing, but was far less potent than the original difelikefalin, suggesting that a dose adjustment would be required for it to address chronic conditions in humans.
It's worth noting, however, that when the dosage was increased, the beta01 difelikefalin had a greater impact on pain signals, without the sedative effects of its non-modified version.
The scientists also determined that beta01 produced much less anxiety-like behavior in a maze test and fewer depression-like signs when the animals were subjected to a tail suspension test.
While these findings are preliminary and preclinical, so not yet tested in humans, the fact that the drug already exists and has FDA approval puts it a few steps ahead of a completely novel compound.
And, despite the limitations, this remains a strong proof-of-concept study showing that a single molecular modification can reshape signals from opioid receptors. If these findings translate to humans, they could represent an important step toward safer opioid medicines.
"Together, these results establish a clear structure-function relationship in which specific ligand–receptor interactions fine-tune the conformational landscape of KOR, directing signaling bias," the researchers write in their study.
"Our work demonstrates a successful example of structure-based design of a biased GPCR agonist, leveraging structural, functional, and computational analyses to rationally modify a clinically used ligand for improved signaling selectivity and therapeutic safety."
The research was published in the journal Nature Communications.
Source: Hefei Institute of Physical Science of the Chinese Academy of Sciences
Fact-checked by Mike McRae.
