The ongoing opioid epidemic in the U.S. kills tens of thousands of people every year. Naloxone, sold under the brand name Narcan, has saved countless lives by reversing opioid overdoses. But new and more powerful opioids keep appearing, and first responders are finding it increasingly difficult to revive people who overdose.
The molecular compound described in the paper is a so-called negative allosteric modulator of the opioid receptor. Allosteric modulators are a hot area of research in pharmacology, because they offer a way to influence how the body responds to drugs by fine-tuning the activity of drug receptors rather than the drugs themselves. Co-author Vipin Rangari, PhD, a postdoctoral fellow in the Majumdar lab, did the experiments to chemically characterize the compound.
To do so, they screened a library of 4.5 billion molecules in the lab in search of molecules that bound to the opioid receptor with naloxone already tucked into the receptor's pocket. Compounds representing several molecular families passed the initial screen, with one of the most promising dubbed compound 368. Further experiments in cells revealed that, in the presence of compound 368, naloxone was 7.
However, people who overdose on opioids and are revived with naloxone can experience withdrawal symptoms such as pain, chills, vomiting and irritability. In this study, while the addition of compound 368 boosted naloxone's potency, it did not worsen the mice's withdrawal symptoms. "Developing a new drug is a very long process, and in the meantime new synthetic opioids are just going to keep on coming and getting more and more potent, which means more and more deadly," Majumdar said."Our hope is that by developing a NAM, we can preserve naloxone's power to serve as an antidote, no matter what kind of opioids emerge in the future."Evan S. O’Brien, Vipin Ashok Rangari, Amal El Daibani, Shainnel O. Eans, Haylee R.