Aristotelia alkaloids as probes for the nicotinic acetylcholine receptors
Ended Project Grant Awarded Last action
- Award ID
- F31AT012713
- Recipient
-
University Of Illinois UEI W8XEAJDKMXH3
- Awarding agency
-
National Center for Complementary and Integrative Health
National Institutes of Health, Department of Health and Human Services
- Obligated
- $277,934
Award facts
- Assistance listing
- 93.213 Research and Training in Complementary and Integrative Health
- Completion date
- Place of performance
- Chicago, IL 60612, USA
Award details come from USAspending.gov.
Description
- 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 A3SS4 subtype over the A4SS2 and A7 subtypes. While other A3SS4 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.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | -$13,914 | |
| Amendment | $564 | |
| Amendment | $48,974 | |
| Amendment | $48,974 | |
| Amendment | $1,280 | |
| Amendment | $1,280 | |
| Amendment | $47,694 | |
| Amendment | $47,694 | |
| Amendment | $0 | |
| Amendment | $47,694 | |
| Amendment | $0 | |
| Amendment | $0 | |
| Original award | $47,694 |
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Quick answers
Who received award F31AT012713?
F31AT012713 was awarded to University Of Illinois by National Center for Complementary and Integrative Health (National Institutes of Health) on September 11, 2024.
How much is award F31AT012713 worth?
$277,934 has been obligated on F31AT012713.
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