A team of scientists led by the College of Chemistry's Richmond Sarpong, professor of chemistry, along with the team of Susruta Majumdar (Washington University) and Jay McLaughlin (University of Florida), described this week in Proceedings of the National Academy of Sciences (PNAS) how a molecule that differs from the well-known painkiller morphine by one core atom retains painkilling activity but is less addictive and does not cause respiratory depression in mice. This new molecule could set the stage for the preparation of new painkillers that are less addictive and less likely to cause death.
Respiratory depression, also known as hypoventilation, is a serious condition where breathing becomes too slow or too shallow to effectively exchange oxygen and carbon dioxide. If left untreated, respiratory depression can lead to life-threatening complications such as respiratory arrest (when breathing stops entirely), brain damage, heart attack, coma, and even death.
"By formally replacing an oxygen atom in the core of morphine with a carbon atom bearing two hydrogens through a total synthesis, we have created a variant of morphine that interacts differently with its receptor," said Sarpong. "Ultimately, the difference in interaction with the receptor results downstream in less of the untoward effects of morphine such as addiction and respiratory depression, which is often what leads to death following an overdose."
Just like the adage that a building is built one brick at a time, chemists often talk about building molecules one atom at a time. However, unlike buildings where replacing one brick with another, say of a different color, is unlikely to make a difference in terms of the function of the building, this is not true for molecules. Carbamorphine, designed by examining the interactions of other morphine derivatives with the mu-opioid receptor, is believed to remove a hydrogen bond that likely leads to the unwanted downstream effects.
Image courtesy of Richmond Sarpong.
"Our design is based on an unproven hypothesis, but the changes in function that we observe for carbamorphine compared to morphine is a pleasant surprise and is something that we plan to follow up on in even greater detail," said Sarpong.
Carbamorphine could be the first in a new type of opioid design where a part of the framework of morphine that has not been previously changed is now varied to produce a new set of molecules that could be less addictive and safer if overdosed.
This project began in Sarpong's laboratory as a thought experiment to apply the concept of "single atom editing." This involves making single atom changes to the framework of molecules in morphine to see if safer variants could be prepared.
"Living in the Bay Area, it is hard to ignore the terrible effects that opioid abuse has wrought on our community," said Sarpong. "I wanted to apply the two decades of expertise that my laboratory has built to trying to make a positive difference in this area and I am very happy that we could bring a team together that cares about these issues to investigate a completely new direction for opioid research."