The United States is in the grip of an epidemic. Opioid drugs are powerful pain-relieving medications, but come with a high risk of addiction. According to the Centers for Disease Control and Prevention, 91 Americans die each day from opioid overdoses, and that figure is rising.
Researchers in economics, psychology, and medicine are all working to combat the epidemic, but perhaps the frontline science is chemistry. By closely examining the underlying structures of the body’s opioid receptors, chemists can drive the development of safer drugs that treat pain effectively but are less likely to lead to addiction and abuse.
Susruta Majumdar is a medicinal chemist in the Sloan Kettering Institute (SKI) at Memorial Sloan Kettering. For more than a decade, Dr. Majumdar has collaborated with SKI molecular pharmacologists Gavril Pasternak and Ying Xian Pan to develop potent, safer analgesic drugs that lack overdose or addictive potential. The three are part of a multicenter group of researchers using structural and chemical biology to identify new targets for pain killers and to design new molecules to relieve pain. This year, the group published a paper[1] in Cell that reports an inventive approach for developing safer opioid drugs. Here, Majumdar discusses the research.
Why do opioid drugs have such potential for causing addiction and abuse?
All the opioid drugs currently available target what is called the mu opioid receptor. These drugs include morphine, oxycodone and fentanyl. When they bind to this receptor, which is found in nerve cells all over the body, they block the pathways that transmit pain signals to the brain.
But targeting the mu receptor also has another effect on the nervous system, causing a feeling of euphoria—a high similar to when you have sex, eat chocolate or take recreational drugs such as cocaine. One of the reasons people become addicted to opioids is because they’re constantly seeking that high.
How does your research address the issue of opioid addiction and abuse?
In addition to mu, there are two other opioid receptors that also block pain signals: the kappa and delta receptors. My research is focused on looking for ways to activate the kappa receptor. We think this approach has great potential. Drugs that target the kappa receptor can block pain signals without giving the feeling of euphoria that leads to abuse.
Kappa drugs that have been studied in the lab have also been found to cause unwanted side effects. These include frequent urination and, more seriously, hallucinations and dysphoria—or feelings of unhappiness. Our goal is to design kappa drugs that provide pain relief while avoiding these negative effects.
What is your strategy for investigating kappa drugs?
We’re using an approach called structure-based drug design. It’s built on the idea that once we know the shape of a protein, we can design a molecule that will fit into it exactly the way we want it to, like a key fitting into a lock.
In this case, the protein is the kappa opioid receptor. If we can determine the receptor’s shape, we can design drugs that bind to it in just the right way.
What does the Cell study add to this area of research?
In 2015, our team discovered a compound that bound to all three opioid receptors with picomolar affinity (that is, very strong binding), and with moderate selectivity for kappa receptors. We found that this molecule had the ability to reduce pain without the other negative effects associated with kappa opioids. We called the compound MP1104, and used it as the starting point to learn more about how to selectively activate the kappa receptor and thus elucidate the molecular mechanisms of kappa opioid actions.
We collaborated with a team led by pharmacologist Bryan Roth at the University of North Carolina (UNC) at Chapel Hill. Roth’s team used MP1104 to crystalize the kappa opioid receptor and determine its structure. Once we had the structure, our lab at SKI could develop a library of other molecules related to MP1104 using structure-based drug design.
MP1104 has made it possible to understand how kappa receptors are activated. And now that we have the crystal structure, we—and other research teams—will be able to discover new kappa drugs that can relieve pain without causing unhappy feelings.
What are the next steps in moving this research forward?
We are continuing our collaboration with UNC. Using structure-based design, we have created analogs of MP1104 that target the kappa opioid receptor. The new compounds were synthesized by SKI research scholar Rajendra Uprety and tested by postdoctoral researcher Tao Che at UNC. At least one of the molecules shows an ability to bind selectively to the kappa receptor over other opioid receptors.
We have also used structure-based design to find analogs of MP1104 that target the mu opioid receptor but that don't cause respiratory distress or physical dependence in mouse models.
Furthermore, we have worked with behavioral pharmacologist Jay P. McLaughlin at the University of Florida to show that MP1104 can block cocaine addiction in mice. If our new compounds have the potential to treat addiction to drugs, including cocaine and alcohol, then that is another important area to pursue.
Our ultimate goal is to find the best opioid candidates and to evaluate them in people.
This research was funded by the National Institutes of Health and its National Cancer Institute, National Institute of Mental Health (NIMH), and National Institute on Drug Abuse and Department of Defense. It was also supported by a NIMH Psychoactive Drug Screening Program Contract, the Michael Hooker Distinguished Chair of Pharmacology at UNC, the Mayday Fund, and the Peter F. McManus Trust.
