# Deconvolution of Galbulimima bark pharmacology through chemical synthesis and target assignment

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2023 · $276,925

## Abstract

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.

## Key facts

- **NIH application ID:** 10682293
- **Project number:** 1R01AT012075-01A1
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Laura M. Bohn
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $276,925
- **Award type:** 1
- **Project period:** 2023-06-08 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10682293

## Citation

> US National Institutes of Health, RePORTER application 10682293, Deconvolution of Galbulimima bark pharmacology through chemical synthesis and target assignment (1R01AT012075-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10682293. Licensed CC0.

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