Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Opioid analgesics and stemmadenine-based alkaloids.
Figure 2: Development of a synthesis strategy for conolidine inspired by the biosynthetic proposal for the conversion of stemmadenine to vallesamine.
Figure 3: Execution of a synthesis pathway to conolidine (1).
Figure 4: Asymmetric synthesis of (+)- and (−)-conolidine.
Figure 5: Conolidine is antinociceptive in visceral, tonic and persistent pain models and is present at micromolar levels in the brain after systemic injection.

References

  1. Melnikova, I. The pain market. Nat. Rev. Drug Discov. 9, 589–590 (2010).

    CAS  Article  Google Scholar 

  2. Crofford, L. J. Adverse effects of chronic opioid therapy for chronic musculoskeletal pain. Nat. Rev. Rheum. 6, 191–197 (2010).

    CAS  Article  Google Scholar 

  3. Kam, T.-S., Pand, H.-S., Choo, Y.-M. & Komiyama, K. Biologically active ibogan and vallesamine derivatives from Tabernaemontana divaricata. Chem. Biodivers. 1, 646–656 (2004).

    CAS  Article  Google Scholar 

  4. Pratchayasakul, W., Pongchaidecha, A., Chattipakorn, N. & Chattipakorn, S. Ethnobotany & ethnopharmacology of Tabernaemontana divaricata. Indian J. Med. Res. 127, 317–335 (2008).

    CAS  PubMed  Google Scholar 

  5. Ingkaninan, K., Ijzerman, A. P., Taesotikul, T. & Verpoorte, R. Isolation of opioid-active compounds from Tabernaemopntana pachysiphon leaves. J. Pharm. Pharmacol. 51, 1441 (1999).

    CAS  Article  Google Scholar 

  6. Scott, A. I., Yeh, C.-L. & Greenslade, D. Laboratory model for the biosynthesis of vallesamine, apparicine, and related alkaloids. J. Chem. Soc. Chem. Commun. 947–948 (1978).

  7. Lim, D-H., Low, T-Y. & Kam, T-S. Biomimetic oxidative transformations of pericine: partial synthesis of apparicine and valparicine, a new pentacyclic indole alkaloid from Kopsia. Tetrahedron Lett. 47, 5037–5039 (2006).

    CAS  Article  Google Scholar 

  8. Ahond, A., Cavé, A., Kan-Fan, C., Langlois, Y. & Potier, P. The fragmentation of N,N-dimethyltryptamine oxide and related compounds: a possible implication in indole alkaloid biosynthesis. J. Chem. Soc. Chem. Commun. 517 (1970).

  9. Hoffmann, R. W. Allylic 1,3-strain as a controlling factor in stereoselective transformations. Chem. Rev. 89, 1841–1860 (1989).

    CAS  Article  Google Scholar 

  10. Bennasar, M.-L., Zulaica, E., Solé, D., Roca, T., García-Díaz, D. & Alonso, S. Total synthesis of the bridged indole alkaloid apparicine. J. Org. Chem. 74, 8359–8368 (2009).

    CAS  Article  Google Scholar 

  11. Amat, M., Dolors Coll, M., Passarella, D. & Bosch, J. An enantioselective synthesis of the Strychnos alkaloid (−)-tubifoline. Tetrahedron: Asymmetry 7, 2775–2778 (1996).

    CAS  Article  Google Scholar 

  12. Amat, M., Dolors Coll, M., Bosch, J., Espinosa, E. & Molins, E., Total syntheses of the Strychnos indole alkaloids (−)-tubifoline, (−)-tubifolidine, and (−)-19,20-dihydroakuammicine. Tetrahedron: Asymmetry 8, 935–948 (1997).

    CAS  Article  Google Scholar 

  13. Kolundzic, F. & Micalizio, G. C. Synthesis of substituted 1,4-dienes by direct alkylation of allylic alcohols. J. Am. Chem. Soc. 129, 15112–15113 (2007).

    CAS  Article  Google Scholar 

  14. Still, W. C. & Mitra, A. A highly stereoselective synthesis of Z-trisubstituted olefins via [2,3]-sigmatropic rearrangement. Preference for a pseudoaxially substituted transition state. J. Am. Chem. Soc. 100, 1927–1928 (1978).

    CAS  Article  Google Scholar 

  15. Hart, S. A., Trindle, C. O. & Etzkorn, F. A. Solvent-dependent stereoselectivity in a Still–Wittig rearrangement: an experimental and ab initio study. Org. Lett. 3, 1789–1791 (2001).

    CAS  Article  Google Scholar 

  16. Wang, X. J., Hart, S. A., Xu, B., Mason, M. D., Goodell, F. R. & Etzkorn, F. A. Serine-cis-proline and serine-trans-proline isosteres: stereoselective synthesis of (Z)- and (E)-alkene mimics by Still–Wittig and Ireland–Claisen rearrangements. J. Org. Chem. 68, 2343–2349 (2003).

    CAS  Article  Google Scholar 

  17. Fristad, W. E. & Paquette, L. A. Oxidation chemistry of a cis-2-(3-flurylidene)ethanol. Heterocycles 31, 2219–2224 (1990).

    CAS  Article  Google Scholar 

  18. Le Bars, D., Gozariu, M. & Cadden, S. W. Animal models of nociception. Pharmacol. Rev. 53, 597–652 (2001).

    CAS  PubMed  Google Scholar 

  19. Collier, H. O. J., Dinneedn L. C., Johnson, C. A. & Schneider, C. The abdominal constriction response and its suppression by analgesics in the mouse. Br. J. Pharmac. Chemother. 32, 295–310 (1968).

    CAS  Article  Google Scholar 

  20. Mogil, J. S., Kest, B., Sadowski, B. & Belknap, J. K. Differential genetic mediation of sensitivity to morphine in genetic models of opiate antinociception: influence of nociceptive assay. J. Pharmacol. Exp. Ther. 276, 532–544 (1996).

    CAS  PubMed  Google Scholar 

  21. Dubuisson, D. & Dennis, S. G. The formalin test: a quantitative study of the analgesic effects of morphine, meperidine, and brain stem stimulation in rats and cats. Pain 4, 161–174 (1977).

    CAS  Article  Google Scholar 

  22. McNamara, C. R. et al. TRPA1 mediates formalin-induced pain. Proc. Natl Acad. Sci. USA 104, 13525–13530 (2007).

    CAS  Article  Google Scholar 

  23. Woolf, C. J. Evidence for a central component of post-injury pain hypersensitivity. Nature 306, 686–688 (1983).

    CAS  Article  Google Scholar 

  24. Tjølsen, A., Berge, O. G., Hunskaar, S., Rosland, J. H. & Hole, K. The formalin test: an evaluation of the method. Pain 51, 5–17 (1992).

    Article  Google Scholar 

  25. Li, X., Kamenecka, T. M. & Cameron, M. D. Bioactivation of the epidermal growth factor receptor inhibitor gefitinib: implications for pulmonary and hepatic toxicities. Chem. Res. Toxicol. 22, 1736–1742 (2009).

    CAS  Article  Google Scholar 

  26. Wess, J. et al. Muscarinic receptor subtypes mediating central and peripheral antinociception studied with muscarinic receptor knockout mice: a review. Life Sci. 72, 2047–2054 (2003).

    CAS  Article  Google Scholar 

  27. Stone, L. S., Fairbanks, C. A. & Wilcox, G. L. Moxonidine, a mixed alpha(2)-adrenergic and imidazoline receptor agonist, identifies a novel adrenergic target for spinal analgesia. Ann. NY Acad. Sci. 1009, 378–385 (2003).

    CAS  Article  Google Scholar 

  28. Jann, M. W. & Slade, J. H. Antidepressant agents for the treatment of chronic pain and depression. Pharmacotherapy 27, 1571–1587 (2007).

    CAS  Article  Google Scholar 

  29. Shimoyama, N., Shimoyama, M., Davis, A. M., Inturrisi, C. E. & Elliot, K. J. Spinal gabapentin is antinociceptive in the rat formalin test. Neurosci. Lett. 222, 65–67 (1997).

    CAS  Article  Google Scholar 

  30. Hunter, J. C. et al. The effect of novel anti-epileptic drugs in rat experimental models of acute and chronic pain. Eur. J. Pharmacol. 324, 153–160 (1997).

    CAS  Article  Google Scholar 

  31. Munro, G. Pharmacological assessment of the rat formalin test utilizing the clinically used analgesic drugs gabapentin, lamotrigine, morphine, duloxetine, tramadol and ibuprofen: influence of low and high formalin concentrations. Eur. J. Pharmacol. 605, 95–102 (2009).

    CAS  Article  Google Scholar 

  32. Baillie, J. K. & Power, I. The mechanism of action of gabapentin in neuropathic pain. Curr. Opin. Investig. Drugs 7, 33–39 (2006).

    CAS  PubMed  Google Scholar 

  33. Goldstein, A. & Sheehan, P. Tolerance to opioid narcotics. I. Tolerance to the “running fit” caused by levorphanol in the mouse. J. Pharmacol. Exp. Ther. 169, 175–184 (1969).

    CAS  PubMed  Google Scholar 

  34. Wise, R. A. & Bozarth, M. A. A psychomotor stimulant theory of addiction. Psychol. Rev. 94, 469–492 (1987).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We gratefully acknowledge T.-S. Kam (University of Malaya, Kuala Lumpur, Malaysia) for providing authentic spectra of natural (+)-conolidine for comparison with our synthetic samples (see Supplementary Information).

Author information

Authors and Affiliations

Authors

Contributions

G.C.M. conceived, initiated and directed the project. M.A.T. and A.K.B. conducted all chemical experiments. L.M.B. initiated and directed the in vivo and in vitro pharmacological evaluation. L.M.B. and M.D.C. directed the pharmacokinetic experiments, and K.M.R. and C.G. conducted all biochemical and in vivo experiments. Receptor binding profiles were generously provided by the National Institute of Mental Health's Psychoactive Drug Screening Program, Contract no. HHSN-271-2008-00025-C (NIMH PDSP). The NIMH PDSP is directed by Bryan L. Roth (MD, PhD) at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscol at NIMH, Bethesda, Maryland, USA. G.C.M. and L.M.B. wrote the manuscript.

Corresponding authors

Correspondence to Laura M. Bohn or Glenn C. Micalizio.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information

Supplementary information (PDF 1238 kb)

Rights and permissions

Reprints and Permissions

About this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nchem.1050

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing