# The design and synthesis of tetracaine derivatives as enhanced ion channel blockers

> **NIH NIH R15** · WILLAMETTE UNIVERSITY · 2020 · $425,626

## Abstract

SUMMARY
Ion channels play an essential role in many biological functions and have been implicated in multiple diseases.
As such, there is a need for new potent, bioactive small molecules that can act as ion channel blockers and as
probes for biomedical research. Tetracaine is a known small molecule ion channel blocker that binds to diverse
molecular targets. The objective of this project is to develop tetracaine derivatives as reversible ion channel
antagonists with high affinity, longer lifetimes, and high selectivity for cyclic nucleotide-gated (CNG). The long-
term goal is developing an understanding of the structure-activity relationships of tetracaine to design new
therapeutics for blinding retinal diseases, such as retinitis pigmentosa (RP). CNG channel blockers have shown
great promise for treatment of RP, but there is a critical need for the development of a new generation of blockers
with greater selectivity for rod CNG channels and ease of delivery. The project will test the central hypothesis
that modifying the three main regions of tetracaine will improve ion channel block by enhancing the affinity,
selectivity, and lifetime of the molecule in biological systems. The objective of this project will be accomplished
by three specific aims: (1) Tetracaine derivatives with enhanced potency for blocking CNG channels will be
synthesized. The tail region will be altered to elucidate the role of the aniline proton as well as to optimize binding.
The aromatic core will be modified with electron-withdrawing substituents, both exocyclic and endocyclic, to
enhance affinity, selectivity, and water solubility. The effect of modifying the lipophilicity of the tail and the position
of substitution on channel binding affinity and selectivity will also be measured. All derivatives will be tested for
potency as blockers of human rod and cone CNG channels using patch-clamp electrophysiology following
expression in the Xenopus oocyte system. (2) Tetracaine derivatives will be created with increased lifetimes and
enhanced hydrolytic stability. To reduce the rate of tetracaine metabolism due to hydrolysis of the ester linkage,
tetracaine derivatives with a modified head-linkage group, including an inverted ester and amide head linkage,
will be generated to take advantage of enzyme specificity. In an attempt to better understand the role of the
carbonyl group, it will be replaced with ether and amine functionalities. The hydrolysis rates will be measured via
a butyrylcholinesterase assay. (3) Promising derivatives will be tested for their effects on retinal function using
electroretinography following injection into the eye. This will allow us to determine their ability to block light
signaling in rod vs. cone photoreceptors and their lifetime within the eye. Finally, derivatives will be tested for
their ability to slow the disease progression in a mouse model of RP. This project is designed to enhance the
research experience of students at Willamette Univers...

## Key facts

- **NIH application ID:** 9965527
- **Project number:** 1R15GM132845-01A1
- **Recipient organization:** WILLAMETTE UNIVERSITY
- **Principal Investigator:** Andrew Duncan
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $425,626
- **Award type:** 1
- **Project period:** 2020-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9965527

## Citation

> US National Institutes of Health, RePORTER application 9965527, The design and synthesis of tetracaine derivatives as enhanced ion channel blockers (1R15GM132845-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9965527. Licensed CC0.

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