Article | Published:

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

Nature Chemistry volume 3, pages 449453 (2011) | Download Citation

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.

  • Compound C17H18N2O

    (+)-Conolidine

  • Compound C17H18N2O

    (-)-Conolidine

  • Compound C16H18N2O

    (S,E)-3-Ethylidene-1-(4-methoxybenzyl)piperidin-4-yl)(1H-indol-2-yl)methanone

  • Compound C15H21NO2

    (±)-(N-(4-Methoxybenzyl)-1,2,5,6-tetrahydropyridin-3-yl)ethanol

  • Compound C15H21NO2

    (R)-(N-(4-Methoxybenzyl)-1,2,5,6-tetrahydropyridin-3-yl)ethanol

  • Compound C15H21NO2

    (S)-(N-(4-Methoxybenzyl)-1,2,5,6-tetrahydropyridin-3-yl)ethanol

  • Compound C28H49NO2Sn

    (S)-(1-(4-Methoxybenzyl)-5-(1-((tributylstannyl)methoxy)ethyl)-1,2,3,6-tetrahydropyridine

  • Compound C7H9NO

    1-(Pyridin-3-yl)ethanol

  • Compound C16H23NO2

    (S,E)-(3-Ethylidene-1-(4-methoxybenzyl)piperidin-4-yl)methanol

  • Compound C16H21NO2

    (S,E)-3-Ethylidene-1-(4-methoxybenzyl)piperidine-4-carbaldehyde

  • Compound C30H32N2O4S

    (S,E)-3-Ethylidene-1-(4-methoxybenzyl)piperidin-4-yl)(1-(phenylsulfonyl)-1H-indol-2-yl)methanol

  • Compound C24H28N2O2

    (S,E)-3-Ethylidene-1-(4-methoxybenzyl)piperidin-4-yl)-1H-indol-2-yl)methanol

  • Compound C24H26N2O2

    (S,E)-3-Ethylidene-1-(4-methoxybenzyl)piperidin-4-yl)-1H-indol-2-yl)methanone

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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

Affiliations

  1. Department of Chemistry, The Scripps Research Institute, Jupiter, Florida, USA

    • Michael A. Tarselli
    • , Alex K. Brasher
    •  & Glenn C. Micalizio
  2. Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida, USA

    • Kirsten M. Raehal
    • , John M. Streicher
    • , Chad E. Groer
    • , Michael D. Cameron
    •  & Laura M. Bohn
  3. Department of Neuroscience, The Scripps Research Institute, Jupiter, Florida, USA

    • Kirsten M. Raehal
    • , John M. Streicher
    • , Chad E. Groer
    •  & Laura M. Bohn

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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.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

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

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DOI

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

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