Deconvolution of Galbulimima bark pharmacology through chemical synthesis and target assignment

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Abstract The Galbulimima (GB) alkaloids are derived from the bark of the Galbulimima genus, which features in the traditional medicine and ritual of Papua New Guinea. GB alkaloid content varies markedly among individual trees, and only some bark samples cause hallucination. The number of alkaloids contained in the bark and their general scarcity complicate identification of the biomolecular targets and rigorous pharmacological characterization. Here we describe new chemical platforms for procurement of each Galbulimima alkaloid, the first new biological targets identified in over three decades and preliminary interrogation by pharmacology and structural biology. Viability of the synthetic platform is supported by route that reduce synthetic burden approximately three-fold. The first section of the grant demonstrates gram-scale Class Ia/b GB alkaloid accession by ligand-controlled cross-electrophile coupling (XEC). This strategy allows modular assembly of the carbocyclic (decalin) core with a variety of piperidine side-chains—motifs that define GB alkaloids. Whereas Class Ia targets mAChRs, scaffold rearrangement to Class Ib changes GPCR selectivity to ORs. Preliminary data suggests oxidized analogs shift OR antagonism toward agonism; in vivo data demonstrates rapid penetration of the brain to affect mouse behavior. Full interrogation of pharmacology and structural characterization of ligand-receptor complexes have begun to identify unique aspects of the "GB opioids." The second section explores gram-scale syntheses of Class II–IV via conversion of high fraction aromatic (FAr) scaffolds to high fraction sp3 (Fsp3), stereochemically-rich natural products. New cross-coupling reactions assemble aromatic feedstocks efficiently; we propose asymmetric variants to render existing racemic routes enantioselective. Importantly, existing and proposed routes are highly divergent and allow exploration of how structural variation correlates to selectivity among a human receptors. We identify another high affinity receptor associated with antispasmodic alkaloids and propose the syntheses of high-priority bradycardia agents. The synthetic platform outlined here combined with advances in robust cell-based second messenger assays now widely available for the receptor families of interest allow unprecedented ability to probe structure, function and selectivity of the GB alkaloids. Ultimately, we expect to identify enough ligand-receptor pairs to begin building a GB alkaloid-receptor interactome to predict structure-function relationships, supported by high-resolution experimental structures. This research holds great potential to identify privileged new scaffold leads for therapeutic development from plant metabolites already validated in humans.