A large percentage of American adults suffer from some sort of severe or chronic pain. According to data from the 2012 National Health Interview Survey, 11.2 percent (25.3 million people) have experienced some form of pain every day for the past three months. In fact, pain is a common reason for patients to seek care from their healthcare professionals.
Although opiate therapy is highly effective in the control of pain, physicians are becoming more cautious in prescribing these narcotics. The majority of drug overdose deaths (more than 6 out of 10) involve an opioid — since 1999, the number of overdose deaths involving opioids has quadrupled — and 2 million people had a substance use disorder involving prescription pain relievers in 2015.
Although the crackdown on pain medication prescribing is intended to help the addiction crisis, pain patients often are left unsupported and in untenable situations.
Chemists are responding to the opioid epidemic by developing powerful opioid detectors to help law enforcement officers quickly identify the drugs on the street and by developing tamper-resistant pills as well as novel, nonopioid analgesics. But scientists are going a step further by focusing on building a better opioid that relieves pain without causing addiction.
According to Bryan Roth, M.D., Ph.D., a professor in the Department of Pharmacology at UNC-Chapel Hill, to create better opioids, it's necessary to know their receptors. Roth's lab studies all aspects of structure and function of these receptors, ranging from the atomic-level analysis of ligand-receptor interactions to in vivo studies, and his recent publications can be found here.
This is an illustration of the active state kappa opioid receptor (KOR) bound to a morphine derivative (purple). (Image: Daniel Wacker, Ph.D., and Tao Che, Ph.D., Roth Lab)
In this three-year study, Roth and colleagues found the crystal structure of the activated kappa opioid receptor (KOR) in the pain-killing drug. Receptors are proteins on the surface of cells.
About 40 percent of drugs currently on the market target G-protein coupled receptors, or GPCRs, such as KORs. The issue is that drugs that hit KORs can have other side effects, such as hallucinations, dysphoria, anxiety and depression.
The scientists needed to know how the receptor was activated to determine the best way to bind a compound to KORs to only relieve pain. Previously, scientists solved the chemical structure of proteins using a technique called X-ray crystallography, but the entire process becomes difficult because opioid receptors are so small and delicate.
Here, the researchers solved this difficulty by using Lipidic Cubic Phase crystallization, suspending KOR molecules in specially designed water-lipid mixtures and then slowly removing the water and using a tiny antibody to prop up the receptor in its active state bound to a ligand — a derivative of morphine.
They then used computer models of ligands to determine which parts they could chemically modify to make the ligands more likely to bind tightly to KORs but not to other receptors. Finally, they synthesized a new compound and showed that it is extremely selective for KORs in lab tests.
This landmark study suggests it is possible to design new drugs based on this active KOR structure, manipulating or tweaking them to only have the desired pain relief effects. Other collaborators of this study are from RTI International, the University of Southern California, Virginia Commonwealth University, Arizona State University, the Institute of Natural Resources and Environmental Audits in China, and Vrije Universiteit Brussels in Belgium.
