Non-opioid compound developed that provides innovative pain relief

Compound 194 Reduces NaV1.7 currents

This image shows the structure of compound 194 (yellow sticks) superimposed on an electrophysiological trace showing reduced sodium currents (yellow vs. black lines) from cells treated with compound 194. The structure illustrates the predicted interaction of CRMP2 (pink, PDB 2GSE) with the Nav1.7 channel (cyan, PDB 6J8G). Credit: University of Arizona Health Sciences

Researchers targeted a common sodium ion channel to reverse pain, with positive results that could lead to a non-addictive pain management solution.

Researchers at the University of Arizona Health Sciences are closer to developing safe and effective non-opioid pain relief after a study showed that a new compound they created reduces pain sensation by regulating a biological channel associated with pain.

Most people experience pain at some point in their lives, and the National Institutes of Health estimates that 100 million people in the United States suffer from chronic pain. About 21-29% of patients prescribed opioids for chronic pain abuse them, and 8-12% of people who use an opioid for chronic pain develop an opioid use disorder, according to the National Institute on Drug Abuse. In 2019, nearly 50,000 people in the United States died from opioid-involved overdoses.

“The discovery of drugs for chronic pain is at the forefront of this research, and it is reinforced by the intersection of COVID-19 the pandemic and the opioid epidemic, ”said Rajesh Khanna, PhD, associate director of the UArizona Health Sciences Comprehensive Pain and Addiction Center and professor of pharmacology at the UArizona College of Medicine – Tucson. “Detecting drugs is a very cumbersome process. Our laboratory looked at a basic pain mechanism, found a way to differentiate it from those before us, and found a compound that has the potential as a new non-opioid treatment for pain. “

Rajesh Khanna

Rajesh Khanna, PhD, is Associate Professor of the University of Arizona Health Sciences Comprehensive Pain and Addiction Center and Professor of Pharmacology at the UArizona College of Medicine – Tucson. Credit: University of Arizona Health Sciences / Kris Hanning

The article, “Selective Targeting of NaV1.7 via Inhibition of CRMP2-Ubc9 Interaction Reduces Pain in Rodents,” was published today (November 10, 2021) in Science translational medicine.

The biological mechanism at the heart of the research is NaV1.7, a sodium ion channel that was previously linked to pain perception through genetic studies of people with rare pain disorders.

Nerve cells, or neurons, use electrical currents to send signals to the brain and throughout the body, and sodium ion channels are essential to a cell’s ability to generate these electrical currents. When a neuron is stimulated, the NaV1.7 channel opens, allowing positively charged sodium ions to cross the cell membrane and enter the previously negatively charged cell. The change in charge across the cell membrane generates an electric current, which increases the excitability of the nerve cell and sets in motion a cascade of events leading to pain.

Because NaV1.7 is a human-validated measure of pain, several trials have attempted to stop pain by using sodium ion channel inhibitors to block NaV1.7. No one has been successful. Dr. Khanna and his team took a different approach – instead of blocking NaV1.7, they indirectly wanted to regulate it.

Using a compound, they designed and christened 194, the team successfully regulated NaV1.7 activation in the laboratory using nerve cells from four different species, including humans. In animal models, 194 was effective in reversing pain in six different pain models in both sexes.

Researchers also found that 194 can also promote pain relief by activating the body’s endogenous or naturally occurring opioid system. Once produced, endogenous opioids activate receptors that produce physiological changes such as pain relief. And 194 did so without causing motor performance problems, depressive behavior or addiction.

Finally, Dr. Khanna and the team a synergistic effect when 194 was combined with morphine and gabapentin. This is a promising sign that 194 can also be used in a dose reduction strategy for painkillers that have adverse side effects, including opioids, while maintaining high levels of pain relief.

The science behind 194

Dr. Khanna’s previous research identified a protein, the collapse response mediator protein 2 (CRMP2) and an enzyme, Ubc9, both of which play a role in NaV1.7 activation. CRMP2 is a protein that binds to NaV1.7 and transports it to the cell membrane, where sodium ions are then transferred to the cell. Ubc9 is an enzyme that labels CRMP2 with another protein – a small ubiquitin-like modifying protein – to specifically control the control of NaV1.7.

Based on this knowledge, Dr. Khanna and the team set out to determine if they could directly regulate the activity of NaV1.7 by blocking Ubc9 from interacting with CRMP2. Team members including May Khanna, PhD, Associate Professor of Pharmacology and member of the BIO5 Institute, Vijay Gokhale, PhD, Research Associate Professor at the BIO5 Institute, and Samantha Perez-Miller, PhD, Researcher and Scientist in Department of Pharmacology, examined 50,000 existing small molecules to identify them with a structure similar to Ubc9.

They selected less than 50 of the closest matches, which were then tested in Dr. Khanna’s laboratory to see if their presence would suppress the influx of sodium through NaV1.7. The results were promising, so the team set out to develop a unique, more effective connection.

The result was 194, which UArizona patented and licensed to start Regulonix LLC through Tech Launch Arizona, the UArizona office that commercializes inventions derived from university research. Drs. Khanna and Gokhale founded Regulonix LLC in 2016 to address the growing opioid epidemic by developing new, non-addictive ways to treat pain and commercialize these innovations.

While 194 shows a great promise for pain relief, Dr. Khanna and the team worked with the National Institutes of Healths National Center for Advancing Translational Sciences to optimize the drug. In this case, an NCATS team focuses primarily on improving the half-life of 194 – the time it takes for a drug to halve in your body – and its drug-like properties.

It is an important step in optimizing the drug’s potential as a painkiller and moving on to the next phase, where researchers will apply for Food and Drug Administration approval to begin clinical trials.

Reference: “Selective Targeting of NaV1.7 via Inhibition of CRMP2-Ubc9 Interaction Reduces Pain in Rodents” 10 November 2021, Science translational medicine.

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