New painkillers with less detrimental side effects, based on morphine structure
In a groundbreaking development, a team of scientists at North Carolina State University has made a significant stride in the field of opioid drug design. By replacing an oxygen atom with a carbon (O → CH₂) in the core structure of opioids like morphine, they have created a new analogue called carbamorphine, which shows promising potential for designing safer and more specific painkillers.
This single heavy atom substitution, preserved in the overall scaffold but creating distinct molecular properties, represents a cutting-edge chemical approach. The O-to-CH₂ substitution leads to a different biological activity profile, which could translate into opioids that retain analgesic potency but potentially reduce adverse effects such as addiction, tolerance, or respiratory depression.
The team's conceptual approach, making single core atom changes to the morphine framework, has been hailed by Joshua Pierce, a synthetic chemist at North Carolina State University, as the most significant advance at this stage. The modification was accomplished via a 15-step total synthesis, demonstrating that such precision modifications to complex molecules like morphine are chemically accessible, enabling further medicinal chemistry exploration.
The newly created analogue, carbamorphine, suppresses secondary pathways responsible for addiction and respiratory depression. In animal tests, (+)-carbamorphine did not reduce breathing rate or create addictive behavior patterns, addressing two of the most concerning side effects of morphine use.
The team conducted docking and simulation studies to model the binding behavior of carbamorphine, revealing that (+)-carbamorphine occupies the same binding pocket as (-)-morphine but is significantly twisted relative to the natural compound. This rotation reduces the number of interactions with the receptor and induces a steric clash with key residues on the opposite side of the pocket, which the team propose may explain carbamorphine's moderate potency and suppression of side effects.
The racemic product was separated into its component enantiomers using chiral chromatography, and the sequence also provided easy access to carbacodeine and carbanalorphine for future biological studies. Pierce suggests it would be interesting to couple this modification with some of the known derivatives of morphine to see whether it could be further enhanced and differentiated from these compounds.
Sarpong, a member of the research team, emphasizes the importance of developing synthetic methods to streamline the process of making single-atom changes directly on the core of compounds like morphine. The team's work could pave the way for a new generation of safer, more targeted painkillers, offering hope for those suffering from chronic pain without the fear of debilitating side effects.
- The research team's development of carbamorphine, a new opioid analogue, shows promise in the health-and-wellness sector, particularly for individuals dealing with chronic diseases and medical-conditions, as it suppresses addiction and respiratory depression, which are common side effects of existing opioids.
- In the field of science and medicinal chemistry, the team's innovative method of replacing an oxygen atom with a carbon atom (O → CH₂) in the morphine framework has opened up a new avenue for designing safer, more specific painkillers, contributing significantly to the overall pursuit of improving health-and-wellness.
