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Highly Targeted Opioid Designed to Avoid Side Effects

Head in hands

(Photo by Cristian Newman on Unsplash)

5 January 2018. A pharmacology team decoded complex opioid proteins in the brain to design a compound that can relieve pain, but avoid the dangerous adverse effects causing addiction and overdoses. Researchers from the lab of North Carolina medical school professor Bryan Roth at University of North Carolina in Chapel Hill describe their discovery in yesterday’s issue of the journal Cell (paid subscription required).

The well-documented opioid crisis in the U.S. and elsewhere shows little sign of abating, with much of the problem linked to abuse of opioid pain drugs. A report by the National Academies of Sciences, Engineering, and Medicine in July 2017 spells out the scope of the crisis, with some 2 million Americans age 12 and older addicted to prescription opioid drugs and another 600,000 addicted to heroin.

The most visible and immediate effect of the emergency is the growing number of overdoses and deaths that result. National Institute on Drug Abuse, part of National Institutes of Health, cites data showing more than 90 Americans each day die from opioid overdoses, with an economic burden estimated at $78.5 billion a year from the costs of care, treatment, lost productivity, and criminal justice.

The UNC team led by post-doctoral researchers Daniel Wacker and Tao Che is seeking to unravel the structure of proteins in the brain that respond to opioid drugs to relieve pain, but also cause the unwanted adverse effects. The researchers focused particularly on kappa opioid receptors, or KORs, proteins found on the surface of brain cells, which in their activated state can stop pain signals. Most of today’s opioid pain relievers address these receptors, but also affect other proteins that trigger the undesired effects.

“One of the big ideas is to target KORs,” says Roth in a university statement, “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.”

Wacker, Che, and colleagues first had to overcome the small size and fragility of KORs and opioid receptors in general that make them difficult to analyze with conventional X-ray techniques, to determine their structure in a crystallized form. In addition, the researchers needed to capture the protein’s structure when activated, which differs from its inactive state, particularly in finding the binding location needed for drugs to work on that protein.

The researchers employed a method called lipidic cubic phase crystallization that suspends protein molecules in a mixture of water and lipids, or oils, then removes the water to reveal the protein’s structure. Comparing KORs in their activated to inactive states revealed key structural details, including the region for binding to the protein. The team screened a number of compounds with the potential to bind to this target, and identified a morphine derivative code-named MP1104. Susruta Majumdar at Memorial Sloan-Kettering Cancer Center in New York who discovered MP1104 is a co-author of the paper.

The researchers modified MP1104 to increase its binding ability to KORs, adding a nanoscale component that stabilizes KORs in their activated state, and tested the synthesized compound in lab cultures. The results show the drug candidate binds to KORs as designed, but unlike conventional opioid drugs, bypasses other receptor proteins, suggesting it can relieve pain while avoiding the dangerous side effects. Next steps will likely include testing this compound and related candidates with lab animals.

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