# Selective Positive Allosteric Modulators of a4b2 Nicotinic Receptors

> **NIH NIH R01** · NORTHEASTERN UNIVERSITY · 2024 · $743,548

## Abstract

ABSTRACT
Tobacco addiction remains a leading cause of disease and death worldwide, and an increasing number of never-
smokers are being exposed to nicotine via e-cigarettes. However, the role of specific nicotinic acetylcholine
receptors (nAChR) in nicotine’s behavioral effects remains poorly understood because of the availability of very
few subtype-selective probes, which limit drug development potential. Thus, this proposal aims to develop novel
probes to better understand the function of the different α4β2 subtypes, which have been proposed to underlie
behaviors characteristic of nicotine dependence. The α4β2 nAChR subtypes exhibit two distinct isoforms: α42β23,
which has a high affinity for acetylcholine and nicotine, and α43β22 nAChR, which has a lower affinity for
acetylcholine and nicotine. Our recent findings have suggested that probes selectively targeting the high
sensitivity α42β23 nAChRs may provide a novel, previously undefined understanding of nicotine’s behavioral and
pharmacological actions. Thus, these studies will develop and optimize novel positive allosteric modulators
(PAMs) of the high sensitivity α42β23 nAChRs. Specific Aim 1 will begin by focusing on the synthesis of novel
analogs of desformylflustrabromine (dFBr) and GAT2802 to derive an improved pharmacological profile. Specific
Aim 2 will involve in vitro characterization of novel probes from both structural classes as α42β3 nAChR-selective
PAMs. Thereafter, Specific Aim 3 studies will evaluate ADME/PK profiling of key α42β23 PAMs to eliminate
potential liabilities and identify probes with suitable drug-like properties. Finally, in Specific Aim 4, the most
promising probes will be tested for their efficacy in inducing behaviors characteristic of nicotine’s 42 nAChR
actions in adult male and female mice. Taken together, these studies will develop and validate novel HS-selective
α42β23 PAM probes to better understand the pharmacological effects of α4β2 nAChRs in behaviors characteristic
of nicotine’s actions, which may thereby lead to future therapeutic implications.

## Key facts

- **NIH application ID:** 10999891
- **Project number:** 1R01DA059985-01A1
- **Recipient organization:** NORTHEASTERN UNIVERSITY
- **Principal Investigator:** CHRISTIE D FOWLER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $743,548
- **Award type:** 1
- **Project period:** 2024-08-01 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10999891

## Citation

> US National Institutes of Health, RePORTER application 10999891, Selective Positive Allosteric Modulators of a4b2 Nicotinic Receptors (1R01DA059985-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10999891. Licensed CC0.

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