Synthesis of conolidine, a potent non-opioid analgesic for tonic and persistent pain

Abstract

Management of chronic pain continues to represent an area of great unmet biomedical need. Although opioid analgesics are typically embraced as the mainstay of pharmaceutical interventions in this area, they suffer from substantial liabilities that include addiction and tolerance, as well as depression of breathing, nausea and chronic constipation. Because of their suboptimal therapeutic profile, the search for non-opioid analgesics to replace these well-established therapeutics is an important pursuit. Conolidine is a rare C5-nor stemmadenine natural product recently isolated from the stem bark of Tabernaemontana divaricata (a tropical flowering plant used in traditional Chinese, Ayurvedic and Thai medicine). Although structurally related alkaloids have been described as opioid analgesics, no therapeutically relevant properties of conolidine have previously been reported. Here, we describe 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 non-opioid analgesics in an in vivo model of tonic and persistent pain. The first total synthesis of conolidine — representing the first asymmetric synthesis of a C5-nor-stemmadenine — is described. The chemical synthesis proceeds in just nine steps and gives an 18% overall yield from a commercially available pyridine — an achievement that led to the discovery that (+)-, (–)- and (±)-conolidine are potent non-opioid analgesics.

Cite this article

Tarselli, M., Raehal, K., Brasher, A. et al. Synthesis of conolidine, a potent non-opioid analgesic for tonic and persistent pain. Nature Chem 3, 449–453 (2011). https://doi.org/10.1038/nchem.1050

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