# Aristotelia Alkaloids as Probes for the Nicotinic Acetylcholine Receptors

> **NIH NIH F31** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2024 · $48,974

## Abstract

ABSTRACT
The nicotinic acetylcholine receptors (nAChRs) have been implicated in a variety of central nervous system
(CNS) disorders. However, the significant similarity between subtypes has limited the discovery of subtype-
selective nAChR antagonists. As a result, the pharmacological utility of the nAChRs depends on the development
of improved ligands. Recently, several alkaloids isolated from Aristotelia chilensis were identified as nAChR
antagonists that preferentially antagonize the α3β4 subtype over the α4β2 and α7 subtypes. While other α3β4
antagonists exist, they also have poor pharmacokinetic properties and multiple off-target liabilities, making the
subtype-selectivity the Aristotelia alkaloids possess particularly unique. In addition, preliminary competitive
studies indicate that these alkaloids act through an allosteric mechanism of action, in contrast to other
antagonists that are largely orthosteric ligands or channel blockers. Previous studies of the Aristotelia genus
have identified >30 unique alkaloids, but few studies have been conducted on their biological activity. My central
hypothesis is that these understudied Aristotelia alkaloids are also subtype-selective nAChR antagonists that
operate through an allosteric mechanism of action. To investigate this, in Aim 1, I will extract alkaloids from the
leaves of A. chilensis through a novel countercurrent chromatography approach, isolating known natural
products while also potentially discovering novel alkaloids. In a complementary approach, Aim 2 seeks to access
known Aristotelia alkaloids via a series of biomimetic transformations. Armed with a library of alkaloids, Aim 3 will
evaluate their activity at multiple nAChRs through a functional assay. Competitive inhibition studies will be done
to investigate the potential allosteric mechanism of action, while mutagenetic analysis will identify which residues
on the receptors are crucial for activity and reveal differences between subtypes. While making synthetic
advancements, this research is both innovative and significant as it will be the most extensive biological
evaluation of the Aristotelia alkaloids to date, providing tools to probe the nAChRs as a whole, as the alkaloids
establish an entire class of subtype-selective nAChR ligands.

## Key facts

- **NIH application ID:** 10820953
- **Project number:** 1F31AT012713-01
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Lisa Eliana Rusali
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 1
- **Project period:** 2024-05-16 → 2026-05-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10820953

## Citation

> US National Institutes of Health, RePORTER application 10820953, Aristotelia Alkaloids as Probes for the Nicotinic Acetylcholine Receptors (1F31AT012713-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10820953. Licensed CC0.

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