Opioids have long been recognized as natural substances with significant pharmacological effects. They are used as analgesics to relieve pain, and morphine, which was isolated and synthesized in the early 19th century, is one of the most well-known examples. This substance provides relief for severely ill patients in the terminal stages of disease. However, improper use of opioids can lead to addiction and serious adverse effects such as respiratory depression.

In the USA, opioids were once heavily promoted through the media, resulting in frequent prescriptions for mild health issues. According to the Centers for Disease Control and Prevention (CDC), nearly 645,000 opioid overdose deaths were recorded in the USA between 1999 and 2021. The opioid crisis has also reached Germany, where the main problem is street drugs, especially heroin, which is often mixed with cheaper opioids like fentanyl. While the lethal dose of heroin is 200 milligrams, just two milligrams of fentanyl can be fatal. In 2022, more than 1,000 people in Germany died due to opioid consumption.

Beginning research with a database of 40,000 natural substances
Governments have introduced measures to combat this epidemic, but the rate of opioid addiction remains high. Meanwhile, many suffer from severe pain that needs to be alleviated. Therefore, there is an urgent need for safe analgesics. Researchers from Johannes Gutenberg University Mainz (JGU), with financial support from the Research Training "Life Sciences – Life Writing" funded by the German Research Foundation (DFG), have made progress towards this goal. "The natural product aniquinazoline B, isolated from the marine fungus Aspergillus nidulans, stimulates opioid receptors and could be used instead of opioids in the future," explained Roxana Damiescu, a member of the research team led by Professor Thomas Efferth. 

Detailed laboratory research
In the search for new compounds, the team started with a chemical database containing more than 40,000 natural substances. The goal was to determine how effectively each substance binds to the corresponding receptor, and also to establish whether these substances have the properties needed for a pharmaceutical drug. Compounds must be somewhat water-soluble, for example. This research required computational calculations in the form of approximations, with results becoming more precise as the number of calculations increased. Each substance was subjected to around 750,000 individual calculations. Such a large number of calculations would far exceed the capacity of a standard computer, so the team used the MOGON supercomputer at JGU. The top 100 candidates from these calculations were then assessed using other analytical methods. 

Further research in the laboratory
The resulting ten best compounds underwent laboratory analysis, where they were subjected to biochemical analysis. The first priority was to determine safety. Using preparations of human kidney cells, researchers checked whether a higher concentration of each substance is toxic to the cells and can kill them. Finally, two other aspects also needed to be tested. "We needed to confirm that the high binding energy of the substance to pain receptors, which was predicted by theoretical calculations, actually exists in the real physical world," said Professor Thomas Efferth, head of the Department of Pharmaceutical Biology at JGU. However, binding of the substance to the receptors is not sufficient by itself. The binding must also affect the functionality of the receptors. Therefore, the research team used a second test system to assess the inhibition of biological activity that occurs with the use of opioids. One of the two compounds passed all tests: aniquinazoline B, a substance present in the marine fungus Aspergillus nidulans. "Our research results show that this substance can have similar effects as opioids, but with significantly fewer adverse reactions," concluded Roxana Damiescu. 

The research work was recently published in the journal ChemMedChem.

Source: Johannes Gutenberg-Universität Mainz