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One of the greatest revolutions in the field of pain medication was the isolation of morphine from the opium poppy in the 19th century. Morphine molecules act as painkillers by attaching themselves to the µ-opioid receptor (MOR) in the central nervous system and blocking the brain from sending pain signals to the rest of the body. This potent opioid analgesic also has side effects such as constipation, respiratory depression, and even serious addiction problems.

A new study in the Proceedings of the National Academy of Sciences has found that a single heavy atom replacement in the morphine core structure can transform its pharmacological behavior, resulting in reduced respiratory depression and no evidence of reward behavior—a key component of addiction tendencies—even at high doses.

Based on the insight that core-atom changes to the opioid drug molecule may exhibit biological effects distinct from the parent compound, the researchers developed a 15-step total synthesis of a morphine derivative where an oxygen atom in the E-ring is replaced with a methylene (CH₂) group and called the new derivative carbamorphine.

The opioid-abuse epidemic, also known as the opioid crisis, is a major concern worldwide as its repercussions go beyond health implications. The addictive nature of opioids affects , with overdose deaths exceeding 100,000 each year, especially from fentanyl, an opioid 50 to 100 times more potent than morphine. The side effects of overuse can also creep into one's social life, often leading to difficulty in maintaining relationships and employment.

With this ongoing opioid crisis, designing morphine-like MOR compounds that relieve pain without causing addiction or breathing problems is a major goal in pain research.

A key interaction that helps morphine activate the opioid receptor is a hydrogen bond between the oxygen atom in its dihydrofuran ring and a tyrosine residue in the receptor.

For nearly two centuries, morphine derivatives like codeine, heroin, and naloxone were developed by making peripheral modifications to the molecule's structure and not the core E-ring oxygen atom. Analogs like levorphanol and dextrorphan that did make changes to the core atom also included other structural changes, making it difficult to pinpoint the impact of removing just a single atom on the morphine-receptor interaction.

To study the role of this bond, the team replaced the core E-ring oxygen with a carbon by introducing a methylene group, a swap that removed the hydrogen bond but kept the molecule's overall size and shape almost identical.

The researchers used cell-based assays to measure how well the molecules bound to and activated the opioid receptor. They found that the carbamorphine molecule showed MOR activity in both enantiomeric forms—two molecules with the same molecular formula and structure but arranged differently—unlike morphine, which has only one enantiomer that is opioid-active.

They also conducted studies in mice to assess the behavioral and physiological effects of the derivative. The results revealed that carbamorphine provided effective pain relief, significantly reduced slow and shallow breathing behavior, and, most importantly, the drug did not show conditioned place preference (CPP)—a behavioral procedure used to assess the rewarding effects of drugs— even at higher doses, indicating a reduced potential for abuse.

These findings highlight how subtle atomic changes can significantly alter a drug's interaction with its receptor and its effects in the body.

The researchers noted that derivatives of opioids that focus on core atom modification could unlock a new generation of safer opioid drugs with more desirable properties.

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