And in the early-but-interesting category, Scripps Research Institute scientists reported the laboratory synthesis of conolidine, a scarce, naturally occurring compound originally isolated from the stem bark of Tabernaemontana divaricata, a tropical flowering plant used in traditional Chinese, Ayurvedic, and Thai medicine. Reporting in Nature Chemistry, Michael A. Tarselli and colleagues at the departments of chemistry and neuroscience, said that the compound’s synthesis would enable study of its chemical and pharmacological properties.
The researchers say that although structurally related alkaloids have been described as opioid analgesics, no therapeutically relevant properties of conolidine have previously been reported. They described the first de novo synthetic pathway to this “exceptionally rare” C5-nor stemmadenine natural product, the first asymmetric synthesis of any member of this natural product class, and the discovery that (±)-, (+)-, and (−)-conolidine are potent and efficacious nonopioid analgesics in an in vivo model of tonic and persistent pain.
Pharmacologic studies showed that the new synthetic compound had surprisingly potent analgesic properties. “While it’s not an opiate, it’s nearly as potent as morphine,” said Glenn Micalizio, an associate professor in the department of chemistry.
But Dr. Bohn noted, “While the pain-relieving properties are encouraging, we are still challenged with elucidating the mechanism of action. 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, but that is something of a double-edged sword, she added. “The lack of side effects makes it a very good candidate for development. On the other hand, if there were side effects, they might provide additional clues as to how the compound works at the molecular level.” That remains a mystery.
And despite the long time lines on the horizon, the arduous search for new analgesics may be worth the pain. The pain-management market is growing, albeit relatively slowly, according to GlobalData, providing ample motivation for drug developers. The value of the osteoarthritis therapy market alone was estimated at $4.4 billion in 2010, with expected growth to $5.9 billion in 2018.
Opioid analgesics remain medical mainstays of drug interventions for severe pain. But their liabilities include addiction and tolerance as well as depression of breathing, nausea, and chronic constipation. Due to their suboptimal therapeutic profile, the search for nonopioid analgesics to replace these well-established therapeutics remains a critical pursuit for pharma companies.