Interaction of Cucurbit[7]uril with Oxime K027, Atropine, and Paraoxon: Risky or Advantageous Delivery System?

Jana Zdarova Karasova,Tomas Kucera,Vit Sestak,Jiri Kassa,Zbynek Vecera,Martin Mzik

doi:10.3390/ijms21217883

Jana Zdarova Karasova, Tomas Kucera + Show 4 more

Open Access

https://doi.org/10.3390/ijms21217883

Copy DOI

Abstract

Antidotes against organophosphates often possess physicochemical properties that mitigate their passage across the blood–brain barrier. Cucurbit[7]urils may be successfully used as a drug delivery system for bisquaternary oximes and improve central nervous system targeting. The main aim of these studies was to elucidate the relationship between cucurbit[7]uril, oxime K027, atropine, and paraoxon to define potential risks or advantages of this delivery system in a complex in vivo system. For this reason, in silico (molecular docking combined with umbrella sampling simulation) and in vivo (UHPLC—pharmacokinetics, toxicokinetics; acetylcholinesterase reactivation and functional observatory battery) methods were used. Based on our results, cucurbit[7]urils affect multiple factors in organophosphates poisoning and its therapy by (i) scavenging paraoxon and preventing free fraction of this toxin from entering the brain, (ii) enhancing the availability of atropine in the central nervous system and by (iii) increasing oxime passage into the brain. In conclusion, using cucurbit[7]urils with oximes might positively impact the overall treatment effectiveness and the benefits can outweigh the potential risks.

Highlights

Antidotes against organophosphates (OPs, nerve agents, and pesticides) often possess physicochemical properties that mitigate their passage across the blood–brain barrier
The substantial hydrophilicity of quaternary moieties limits their distribution throughout the body, but these features are essential for the antidotal effect [5,6,7]
The binding effect of CB[7] for the lipophilic part of paraoxon-ethyl and atropine and the aromatic part of K027 could be explained by the replacement of the high-energy water molecules in the free CB[7] [24]

Summary

Introduction

Antidotes against organophosphates (OPs, nerve agents, and pesticides) often possess physicochemical properties that mitigate their passage across the blood–brain barrier. In the past few decades, scientists have been developing drug delivery systems that would overcome the drugs’ non-optimal pharmacokinetic behavior and help them reach their pharmacodynamic targets. In the case of OPs poisoning, the bisquaternary reactivators (briefly named oximes) directly counteract the acetylcholinesterase (AChE, EC 3.1.1.7) inhibition [1,2] and atropine blocks muscarinic receptors [3,4]. The substantial hydrophilicity of quaternary moieties limits their distribution throughout the body (especially the brain), but these features are essential for the antidotal effect [5,6,7]. The development of novel carrier systems should fulfill three essential prerequisites: (i) improve drug bioavailability, (ii) increase targeting, and (iii) diminish a drug’s systemic toxicity.

Methods

Findings

Discussion

Conclusion