# Synthesis and Evaluation of Alkaloids to Probe Membrane Receptors

> **NIH NIH R35** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2023 · $378,177

## Abstract

ABSTRACT
The discovery of new small molecules that perturb the function of membrane receptors, like G-protein coupled
receptors (GPCRs) and ligand-gated ion channels (LGIC), remains critically important to the study and
improvement of human health. Natural products are particularly well-suited for this task, as their structural
complexity and unique mechanism of action make them superior chemical probes and excellent starting points
for drug discovery. The Riley lab is focused on developing step-economic synthetic routes and robust isolation
protocols to access these complex natural product scaffolds. Through modular total syntheses, semi-synthetic
methods, and contemporary receptor assays, we transform natural products into highly potent and selective tools
for studying membrane receptors. This application describes an overview of our work and future directions in
applying these strategies to investigate the nicotinic acetylcholine receptors (nAChRs) and the kappa opioid
receptor (κOR) as representative LGIC and GPCR, respectively. The first research area builds upon our work
that recently identified members of the Aristotelia alkaloid family as potent inhibitors of the nAChRs, a major
class of LGICs, with an unusual yet desirable subtype-selectivity. During this award, we will develop streamlined
synthetic chemistry to access the entire class of Aristotelia alkaloids and generate large libraries of their
derivatives. By coupling these synthetic chemistry efforts with an expanded ability to screen for activity against
an array of nAChR subtypes and other membrane receptors, this work will deliver new chemical tools to probe
the biological function of specific nAChR subtypes. In the second research area, we will explore a novel class of
κOR agonists derived from the indole alkaloid akuammicine that were recently discovered in our laboratory. Our
initial studies identified these akuammicine derivatives are potent biased agonist that preferentially activate the
G-protein signaling pathway. Leveraging isolation protocols that provide synthetically useful quantities of
complex alkaloids directly from their natural sources, we will employ late-state diversification techniques to
rapidly generate novel derivatives that probe ligand-receptor interactions within the κOR and monitor their ability
to initiate opioid signaling cascades. We expect the results from this research will reach beyond the nAChR and
κOR and can be applied to other therapeutically relevant LGICs and GPCRs, thereby having a significant impact
on drug discovery by revealing new directions to rationally design ligands for these important membrane
receptors.

## Key facts

- **NIH application ID:** 10668500
- **Project number:** 5R35GM147005-02
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Andrew Riley
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $378,177
- **Award type:** 5
- **Project period:** 2022-08-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10668500

## Citation

> US National Institutes of Health, RePORTER application 10668500, Synthesis and Evaluation of Alkaloids to Probe Membrane Receptors (5R35GM147005-02). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10668500. Licensed CC0.

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