Scientists Find Natural Product Shows Pain-killing Properties

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The rare natural product central to the study is derived from the bark of a widely grown tropical flowering plant Tabernaemontana divaricata (also known as crepe jasmine). Long part of traditional medicine in China, Thailand and India, extract from the leaves has been used as an anti-inflammatory applied to wounds, while the root has been chewed to fight the pain of toothache. Other parts of the plant have been used to treat skin diseases and cancer.

Conolidine belongs to a larger class of natural products, called C5-nor stemmadenines, members of which have been described as opioid analgesics, despite a substantial discrepancy between potent in vivo analgesic properties and low affinity to opiate receptors. Conolidine is an exceptionally rare member of this family for which no therapeutically relevant properties had ever been described. Despite the potential value of conolidine and related C5-nor stemmadenines as leads for therapeutics, efficient methods to prepare these molecules were lacking.

"This was a classic problem in chemical synthesis," said Glenn Micalizio, an associate professor in the Department of Chemistry, who initiated and directed the study, "which we were able to solve effectively and efficiently - an achievement that made subsequent assessment of the potential therapeutic properties of this rare natural product possible." The pharmacological studies confirmed that while it's not an opiate, it's nearly as potent as morphine.

In various models of pain, the new synthetic compound performed spectacularly, suppressing acute pain and inflammatory-derived pain, two key measures of efficacy. Not only that, but the new compound passed easily through the blood-brain barrier, and was present in the brain and blood at relatively high concentrations up to four hours after injection.

"While the pain-relieving properties are encouraging, we are still challenged with elucidating the mechanism of action," he said. "After pursuing more than 50 probable cellular targets, we are still left without a primary mechanism." So far, the compound has shown remarkably few, if any, side effects.

While the synthetic compound might be as effective as morphine, it doesn't act at any of the receptors associated with opiates. In fact, it misses most of the major neurotransmitter receptors completely, suggesting it may be highly tuned towards relieving pain while not producing multiple side effects. While still in the early stages of development, further characterizations of conolidine may suggest further development as a human therapeutic for the treatment of pain.; Source: Scripps Research Institute