Synthesis and target annotation of the alkaloid GB18

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. A synthetic route to GB18, an alkaloid from the bark of hallucinogenic Galbulimima sp., is developed, enabling its identification as an antagonist of κ- and μ-opioid receptors.