Overlay of the cryo-EM structure of morphine (PDB: 8EF6) and the docked pose of (+)-carbamorphine, key residues in TM3 are labelled.
Researchers at WashU Medicine have developed a modified form of morphine that may offer safer, more effective pain relief. In a study published in Proceedings of the National Academy of Sciences (PNAS), the team showed that changing just one atom in the morphine molecule can significantly reduce the drug’s harmful side effects while still relieving pain.
The research was led by Susruta Majumdar, PhD, a professor in the Department of Anesthesiology, in collaboration with Richmond Sarpong, a professor of chemistry at the University of California at Berkeley. The work in the Majumdar Lab was led by Rohini Ople, PhD, a former postdoctoral fellow, and Nokomis Ramos-Gonzalez, PhD, a current postdoctoral fellow. They developed a new compound called carbamorphine by swapping one oxygen atom in the structure of morphine with a methylene group. “Strikingly, this changed the stereospecificity of binding. Morphine is a natural product derived from opium poppy, papaver somniferum and only the (-)-isomer and not its mirror image is active. In case of carbamorphine the -(-) as well as the unnatural isomer -(+) is active,” said Majumdar.
Although the change seems small, it had a major impact. In lab tests and mouse studies, the synthetic isomer was still able to relieve pain, but unlike regular morphine, it caused much less breathing suppression and didn’t trigger the same reward response in the brain that causes addictive behavior.
This is an important step forward in the search for better, safer opioid medications. Morphine is a powerful and widely used painkiller, but it comes with serious risks, including overdose and addiction.
“One in five Americans lives with chronic pain, and safer, non-addictive options are urgently needed,” said Majumdar.
“Morphine is the gold standard, but our findings show that even a small tweak to its structure could lead to new generation of painkillers that are just as effective, but much less harmful.”
The team plans to continue investigating carbamorphine and related compounds to evaluate their potential for use in human treatments. While more testing is needed, this early research opens the door for new morphine-like compounds that could offer pain relief without the risks of addiction or overdose.