Opioids like morphine, codeine, and opium are effective painkillers, but they also have adverse effects, including addiction, nausea, and constipation. Thus, scientists are actively looking for alternative drugs that would mitigate pain with minimal side effects. Nature serves as a great resource, as there are a large variety of plants with medicinal properties.
In a recent issue of Nature Chemistry, chemists from the Scripps Institute in Florida report that a natural product called conolidine acts as a non-opioid analgesic. Conolidine is one of the many chemicals found in a flowering tropical plant (Tabernaemonta divaricata) that could have medical relevance. Traditional Ayurvedic (native to India), Chinese, and Thai medicines use the tropical plant for treating pain, fever, dysentery, and other diseases.
It is extremely difficult to isolate conolidine from plants, as it is a rare component—scientists have only been able to extract conolidine with about 0.00014 percent yield. In order to study conolidine’s medicinal properties, researchers would need a more efficient way to obtain the pure compound.
Lead author Michael Tarselli led a Scripps team that successfully synthesized conolidine for the first time. They managed to obtain conolidine from a commercially available starting material in nine steps (short for natural product synthesis) with an 18 percent overall yield, which is efficient enough for research purposes.
The synthesis produces a racemic mixture of conolidine, meaning that there are different enantiomers. You can think of enantiomers as non-superimposable mirror images (kind of like your left and right hands) that result from different ways of rotating chemical groups in conolidine. Another eight steps of chemical manipulation allows the authors to resolve the racemic mixture of conolidine into two different enantiomers.
When Tarselli and his colleagues tested the enantiomers of conolidine on mice, they found that the drugs effectively suppress pain that is caused by inflammation. Conolidine also remains in the brain and plasma up to four hours after injection. One of the conolidine enantiomers even showed similar drug potency to morphine in suppressing a chemically induced pain response.
Conolidine appears to be a non-opioid painkiller, as it does not bind to the primary opioid receptor that is targeted by morphine. Furthermore, conolidine had no effect on the locomotor activity of mice, while morphine did. The authors have not yet determined conolidine’s mechanism of action.
Tarselli’s synthesis of conolidine may not be ideal for industrial use, but it can produce enough of the compound for medical researchers. The synthesis also offers flexibility in modifying the chemical structure of conolidine to make different derivatives that may also have analgesic properties.
Nature Chemistry, 2011. DOI: 10.1038/NCHEM.1050
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