Mini review on blood–brain barrier penetration of pyridinium aldoximes

Abstract

This paper reviews the blood-brain barrier (BBB) penetration of newly developed pyridinium aldoximes. Pyridinium aldoximes are highly charged hydrophilic compounds used in the treatment of subjects exposed to organophosphonates because they are effective as acetylcholinesterase reactivators. Pyridinium aldoximes have antidotal effects against poisoning with cholinesterase inhibitors, a frequent problem affecting people working with organophosphate-based insecticides and pesticides. Toxic organophosphonate products such as sarin and tabun can be used by terrorists as chemical warfare agents. This poses a severe challenge to all innocent and peace-loving people worldwide. This review gives a brief summary of BBB transporters and description of the current in vitro and in vivo methods for the characterization of BBB penetration of established and novel pyridinium aldoximes. The authors provide a putative mechanism of penetration, outline some future ways of formulation and discuss the possible advantages and disadvantages of increasing BBB penetration.

Potent 3‐Hydroxy‐2‐Pyridine Aldoxime Reactivators of Organophosphate‐Inhibited Cholinesterases with Predicted Blood–Brain Barrier Penetration

“…[38] Nevertheless, it is anticipated that these 3-hydroxy-2-pyridinea ldoximes will achieve brain concentrations higher than 10 %o ft heir blood concentrations, which is the reported upper limit for the standard oximes. [39] From the structure-activity relationship (SAR) perspective, the most important structurale lement governing the reactivation efficiency of the tested oximes is the moiety that is supposed to be stabilised by residues at the peripheral site. Ad etailed examination of Ta bles 2a nd 3d rew our attention to oximes 16 and 17 both having am orpholine ring that is stabilised at the peripheral site, as observed in the crystal structure of AChE-17 andc orroborated by docking studies of 16,t hereby enabling ap roper positioning of the 3-hydroxy-2-piridine aldoximem oiety for nucleophilic displacement,r egardless of the different steric shield provided by the OPs.…”

Mixed cationic liposomes for brain delivery of drugs by the intranasal route: The acetylcholinesterase reactivator 2-PAM as encapsulated drug model

“…However, current AChE reactivators (quaternary oximes) are unable to reactivate phosphylated AChE in the central nervous system because they do not cross significantly the BBB [29]. Different strategies have been implemented for allowing these reactivators to cross the BBB [30]. In particular, non-quaternary oximes capable of crossing the BBB were synthesized.…”

A comparison of the reactivating and therapeutic efficacy of two novel bispyridinium oximes (K920, K923) with the oxime K203 and trimedoxime in tabun-poisoned rats and mice

“…On the other hand, bispyridinium oximes are less lipophilic than monopyridinium oximes and, therefore, they poorly penetrate across the blood-brain barrier, in maximum of 6% (Lorke et al, 2008;Zdarova Karasova et al, 2010). For this reason, their ability to reactivate tabun-inhibited AChE in the brain is lower compared to the peripheral compartment (Lorke et al, 2008;Kalasz et al, 2015). To eliminate above-mentioned limitation of the effects of AChE reactivators, new analogues of bispyridinium oximes were developed to extend their properties (Berend et al, 2008;Kovarik et al, 2013).…”