Researchers at UNC-Chapel Hill say they have developed a “new drug-like compound” that could lead to better, safer opioids that would relieve severe pain without the side effects of current opioid-based drugs.
The scientists published their findings Thursday in the journal Cell.
In a news release, UNC branded the development as a “big step.”
With the U.S. grappling to manage an opioid addiction crisis, the UNC team says that their discovery demonstrates a “route” to a developing treatments “without causing the severe side effects at the heart of the opioid epidemic.”
For example, on average, three people a day die from opioid overdoses in North Carolina, and that’s just the tip of the iceberg, state officials working on policies and programs to reverse this trend told legislators in November. For every death, there are three hospitalizations, they said
The research focuses on “opioid receptors” on cell surfaces that open the way for pain relief as well as harmful side effects.
Lumen Learnings defines receptors this way:
“Cell-surface receptors, also known as transmembrane receptors, are cell surface, membrane-anchored, or integral proteins that bind to external ligand molecules. This type of receptor spans the plasma membrane and performs signal transduction, converting an extracellular signal into an intracellular signal.”
The “K” target
“To create better opioids, we need to know the structure of their receptors,” said senior author Bryan Roth, MD, PhD, the Michael Hooker Distinguished Professor of Protein Therapeutics and Translational Proteomics in the Department of Pharmacology at UNC-Chapel Hill. “Until recently, this was impossible. But now we know the structure of the activated kappa opioid receptor. And we showed we can actually use the structure to make a drug-like compound with better properties than current opioids.”
A key target is κ-opioid receptor (KOP).
“Tens of thousands people who take opioids die every year, and so we need safer and more effective drugs for treating pain and related conditions,” Roth said. “One of the big ideas is to target KORs because the few drugs that bind to it don’t lead to addiction or cause death due to overdose. Those side effects are mainly related to actions at the mu opioid receptor.”
Summary of the report
Here is the summary of the report as published at Cell:
“The κ-opioid receptor (KOP) mediates the actions of opioids with hallucinogenic, dysphoric, and analgesic activities. The design of KOP analgesics devoid of hallucinatory and dysphoric effects has been hindered by an incomplete structural and mechanistic understanding of KOP agonist actions. Here, we provide a crystal structure of human KOP in complex with the potent epoxymorphinan opioid agonist MP1104 and an active-state-stabilizing nanobody. Comparisons between inactive- and active-state opioid receptor structures reveal substantial conformational changes in the binding pocket and intracellular and extracellular regions. Extensive structural analysis and experimental validation illuminate key residues that propagate larger-scale structural rearrangements and transducer binding that, collectively, elucidate the structural determinants of KOP pharmacology, function, and biased signaling. These molecular insights promise to accelerate the structure-guided design of safer and more effective κ-opioid receptor therapeutics.”