# Novel modulators of the dopamine transporter for alcohol and nicotine use disorders

> **NIH NIH R44** · NAPROGENIX, INC · 2020 · $140,059

## Abstract

Abstract
The parent award is to develop novel medications for alcohol and nicotine use disorders. These
disorders have increased during COVID19 [e.g. Clay and Parker 2020] and are associated with
increased susceptibility to, and severity of, infection. This supplemental proposal is focused on
how mechanisms of COVID-19 infection and neurotoxicity are influenced by alcohol and nicotine,
and how these novel medications interact with these mechanisms. The applicants have previously
used organotypic hippocampal neuronal cultures to study interactions between nicotine, alcohol
withdrawal and viral protein neurotoxicity, and these cultures will be used here. First, nicotine has
been reported to up-regulate the viral “receptor” angiotensin converting enzyme 2 (ACE2) on
neurons, providing a mechanism for increased SARS CoV2 infectivity and neurotoxicity in
smokers and “vapers” [see Kabbani & Olds 2020]. The nicotinic receptor partial agonists
(lobinaline N-oxides) from the parent award should inhibit this effect of nicotine, and this will be
tested in the first specific aim using immunohistochemistry to evaluate ACE2 expression in
organotypic cultures. Once CNS infection has occurred, coronaviruses cause “excitotoxicity” that
is inhibited by inhibitors of neuronal glutamate /NMDA receptors (NMDARs) [Hasanagic &
Serdeveric, 2020]. This is similar to alcohol withdrawal (AWD) [Stepanyan et al, 2008] and so
should be ameliorated by drugs that prevent neurotoxicity in AWD. Once again, the nicotinic
activity of lobinaline N-oxides may be valuable, but another medication under development by the
company for alcohol use disorder, the aryliminoguanidine, JR220, is even more directly relevant
because it is an inhibitory modulator of the NMDAR [Barron et al, 2012], The neuroprotective
possibilities for these drugs will be evaluated against viral protein neurotoxicity in organotypic
cultures in specific aim 2. The hypothesis is therefore that coronavirus infectivity and neurotoxicity
are enhanced in patients with nicotine and alcohol use disorders, and that both the disorders and
the COVID19 consequences should be inhibited by the medications under development. These
novel therapeutic targets for lobinaline N-oxides and JR220 in COVID-19 infection will strongly
support the therapeutic and commercial value of products from the parent award.

## Key facts

- **NIH application ID:** 10236243
- **Project number:** 3R44AA025804-03S1
- **Recipient organization:** NAPROGENIX, INC
- **Principal Investigator:** JOHN M. LITTLETON
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $140,059
- **Award type:** 3
- **Project period:** 2016-09-22 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10236243

## Citation

> US National Institutes of Health, RePORTER application 10236243, Novel modulators of the dopamine transporter for alcohol and nicotine use disorders (3R44AA025804-03S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10236243. Licensed CC0.

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