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Deconvolution of Galbulimima bark pharmacology through chemical synthesis and target assignment

Award Number: R01AT012075
ORGANIZATION: CENTER FOR DRUG EVALUATION AND RESEARCH, NIH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/08/2023
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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Deconvolution of Galbulimima bark pharmacology through chemical synthesis and target assignment - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $663,419 )
2025	2025	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Research and Training in Complementary and Integrative Health	000	3	3/13/2025	NON-COMPETING CONTINUATION	$663,419
														Subtotal = $663,419

Issue Date FY: 2024 ( Subtotal = $1,011,931 )
2024	2024	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Research and Training in Complementary and Integrative Health	002	2	8/20/2024	NON-COMPETING CONTINUATION	$66,054
2024	2024	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Research and Training in Complementary and Integrative Health	001	2	2/23/2024	NON-COMPETING CONTINUATION	$655,042
2024	2023	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Research and Training in Complementary and Integrative Health	000	1	1/19/2024	NEW	$290,835
														Subtotal = $1,011,931

Issue Date FY: 2023 ( Subtotal = $276,925 )
2023	2023	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Research and Training in Complementary and Integrative Health	000	1	6/7/2023	NEW	$276,925
														Subtotal = $276,925

Grand Total All Awards = $1,952,275

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Deconvolution of Galbulimima bark pharmacology through chemical synthesis and target assignment

Award Number: R01AT012075

ORGANIZATION: CENTER FOR DRUG EVALUATION AND RESEARCH, NIH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/08/2023

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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