# Refined uncharged Bis-Oximes for Rapid CNS Reactivation of OP-Inhibited hAChE.

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2023 · $192,670

## Abstract

Refined uncharged bis-oximes for rapid CNS reactivation of OP-inhibited hAChE.
 Project Summary. Reactivation of organophosphate (OP) inhibited acetylcholinesterase
(AChE) by anti-OP antidotes is the only true remedy for OP intoxication in nerve agent or OP
pesticide exposure. Most of currently approved and experimental anti-OP antidotes are
nucleophilic aldoximes that attack and remove phosphorus atom of OPs covalently attached to
the AChE active serine.
 One significant way of improving current antidotal treatment of OP intoxication is by creation
of reactivating antidotes that will reach inhibited AChE in peripheral tissue but also in the CNS,
where currently approved antidotes cannot enter.
 We have designed and characterized in vitro seven improved uncharged LG bis-oxime
antidotes of a novel scaffold, with better reactivation of sarin, cyclosarin, VX and paraoxon
inhibited hAChE than RS194B.
 The uniquely novel feature of the LG bis-oxime scaffold is that ionizable cyclic amines and
aldoxime groups allow single compound to equilibrate between up to sixteen ionic forms differing
in nucleophilic reactivity and in conformation.
 We now propose to explore and structurally optimize this new antidote scaffold, based on our
yet unpublished X-ray structural templates of both LG bis-oximes and of the fastest pyridinium
bis-oxime MMB4. Templates will be informed by inelastic neutron scattering (INS) data. We will
test refined compounds for reactivation potency against OP-hAChE conjugates in vitro and will
evaluate the initial PK profile of most promissing reactivators in mice. Interaction of best refined
candidates with AChE will be explored by X-ray and INS.

## Key facts

- **NIH application ID:** 10582723
- **Project number:** 5R21NS120839-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Zoran Radic
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $192,670
- **Award type:** 5
- **Project period:** 2022-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10582723

## Citation

> US National Institutes of Health, RePORTER application 10582723, Refined uncharged Bis-Oximes for Rapid CNS Reactivation of OP-Inhibited hAChE. (5R21NS120839-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10582723. Licensed CC0.

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