# Development of JR-220 (4-Chlorobenzylidenamino-guanidine hydrochloride) as a medication for alcohol dependence

> **NIH NIH U44** · NAPROGENIX, INC · 2022 · $1,404,983

## Abstract

Abstract
Alcohol dependence affects at least 4% of the US population, with a financial cost in excess of $100Bn.
Prevention of relapse in patients attempting to reduce alcohol consumption is a major therapeutic target, but
current treatments are ineffective, and there is an urgent need for new medications. Major factors in causing
relapse include the protracted symptoms of withdrawal from alcohol, which are relieved by returning to
drinking. Alcohol withdrawal is also implicated in the neurodegeneration that is associated with dependence.
There is abundant evidence that the glutamate/NMDA receptor (NMDAR) is a molecular target in alcohol
withdrawal, and that inhibitory modulators of the NMDAR are potentially valuable as anti-relapse
pharmacotherapy. Target validation identified polyamine enhancement of NMDAR function via the NR2B
subunit as a specific target in alcohol withdrawal, and molecular screening identified several lead compounds.
JR220 was the most active novel compound from an aryliminoguanidine series, and its cellular effects on
neuronal cultures were consistent with NMDAR inhibition via this site. JR220 was then tested in a variety of
rodent screens relevant to alcohol dependence, withdrawal and neurotoxicity, including several screens in
other laboratories. The drug was highly active in all of these screens, with a potency 5-200x that of
acamprosate, which is FDA-approved for the prevention of relapse. JR220 caused mild sedation at higher
doses, but there was no overt toxicity even on repeated administration. Pharmacokinetic studies in the rat
showed dose dependent elevations of concentrations in plasma after intraperitoneal, subcutaneous and oral
administration (oral bioavailability >70%). Concentrations obtained in brain were ~10x higher than plasma,
suggesting an active uptake system at the blood/brain barrier. On repeated once daily dosing for 7 days,
JR220 did not accumulate in plasma or brain, and no overt toxicity was observed. The only concern is that the
plasma half-life following oral administration may be too short for once-a-day dosing in relapse prevention. This
can be addressed by formulation as an oral extended release formulation or by a transdermal patch (which
would also have other advantages for treatment of alcohol use disorders). Intellectual property in JR220 as a
treatment for aspects of alcohol withdrawal and the transdermal patch formulation of JR220 are covered by
provisional applications to the USPTO. The preliminary data indicates that JR220 is an excellent candidate as
an anti-relapse medication, and the current proposal is to develop the drug further for this use. The aim is now
to complete the studies required prior to submission of the drug to the FDA for consideration as an
investigational new drug (IND). Thus, in the proposed studies we will complete investigation of metabolism and
metabolite identification in vitro, and Absorption, Distribution, Metabolism, and Excretion in vivo. The studies
will a...

## Key facts

- **NIH application ID:** 10478126
- **Project number:** 5U44AA026126-04
- **Recipient organization:** NAPROGENIX, INC
- **Principal Investigator:** Cindy Ann Burklow
- **Activity code:** U44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,404,983
- **Award type:** 5
- **Project period:** 2017-08-25 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10478126

## Citation

> US National Institutes of Health, RePORTER application 10478126, Development of JR-220 (4-Chlorobenzylidenamino-guanidine hydrochloride) as a medication for alcohol dependence (5U44AA026126-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10478126. Licensed CC0.

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