Synthesis and target annotation of the alkaloid GB18.
basic_science · Level V
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- Record sourced from PubMed, PMID 35551513.
- Also identified by DOI 10.1038/s41586-022-04840-9 and PMC identifier PMC3723354.
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Abstract
Ingestion of alkaloid metabolites from the bark of Galbulimima (GB) sp. leads to psychotropic and excitatory effects in humans1-4. 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.