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Synthesis and target annotation of the alkaloid GB18

Nature volume 606, pages 917–921 (2022)Cite this article

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Abstract

Ingestion of alkaloid metabolites from the bark of Galbulimima (GB) sp. leads to psychotropic and excitatory effects in humans1,2,3,4. Limited, variable supply of GB alkaloids5, however, has impeded their biological exploration and clinical development6. Here we report a solution to the supply of GB18, a structural outlier and putative psychotropic principle of Galbulimima bark. Efficient access to its challenging tetrahedral attached-ring motif required the development of a ligand-controlled endo-selective cross-electrophile coupling and a diastereoselective hydrogenation of a rotationally dynamic pyridine. Reliable, gram-scale access to GB18 enabled its assignment as a potent antagonist of κ- and μ-opioid receptors—the first new targets in 35 years—and lays the foundation to navigate and understand the biological activity of Galbulimima metabolites.

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Fig. 1: Analysis of structure and synthesis.
Fig. 2: Entry into the GB18 core.
Fig. 3: Completion of rac-1 on gram scale.
Fig. 4: Identification of high potency target receptors of GB18.

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Data availability

All data are made available in the main text or the Supplementary Information, including experimental procedures, copies of NMR spectra and X-ray structure reports. Details regarding materials and methods for all biological assays are available on the PDSP website https://pdsp.unc.edu/ims/investigator/web/. Structural parameters are available from the Cambridge Crystallographic Data Centre (CCDC) under the following reference numbers: SI-2, 2099462; 6, 2096777; 8, 2156368; 3, 2156367; endo-2, 2096779; endo-2·HCl, 2101251; exo-2, 2099728; 11·H2O, 2105522; 12·(CH2Cl2)0.5, 2145022; 14, 2118272; rac-1, 2143708; (+)-1, 2149782; (−)-1, 2086615; ent-2-epi-6-epi-1·HCl, 2099978; L8·HCl·H2O, 2105525.

Code availability

Code used to generate Fig. 4c,d is available in the Supplementary Information (page 72).

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Acknowledgements

Ki determinations, receptor-binding profiles, agonist and antagonist functional data were generously provided by the National Institute of Mental Health's Psychoactive Drug Screening Program, contract no. HHSN-271-2018-00023-C (NIMH PDSP). The NIMH PDSP is directed by B. L. Roth at the University of North Carolina at Chapel Hill and Project Officer J. Driscoll at NIMH, Bethesda. We thank J. Chen, B. Sanchez and Q. N. Wong for assistance with separations and analysis. M. Gembicky, E. Samolova, J. Bailey and the entire UCSD Crystallography Facility are acknowledged for X-ray crystallographic analysis. L. Pasternack and D.-H. Huang are acknowledged for assistance with NMR spectroscopy. We thank S. W. M. Crossley, M. D. Palkowitz, B. P. Smith and G. Tong for proofreading. Support was provided by the National Institutes of Health (R35 GM122606; S10 OD025208), the National Science Foundation (CHE 1856747) and the Skaggs Graduate School (fellowship to S.W.).

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  1. Department of Chemistry, Scripps Research, La Jolla, CA, USA

    Stone Woo & Ryan A. Shenvi

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  1. Stone Woo
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Contributions

R.A.S. and S.W. conceived the project. R.A.S. directed the research. R.A.S. and S.W. composed the manuscript and S.W. compiled the supplementary information. S.W. executed all the experimental work. R.A.S. analysed data and parameterized the synthesis.

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Correspondence to Ryan A. Shenvi.

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A provisional patent has been filed by S.W. and R.A.S.: US patent application no. 63/301,677.

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Experimental procedures, spectral data, biological assay data, chemical informatics data and code, references and crystallographic data.

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Woo, S., Shenvi, R.A. Synthesis and target annotation of the alkaloid GB18. Nature 606, 917–921 (2022). https://doi.org/10.1038/s41586-022-04840-9

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