Small quaternary inhibitors K298 and K524: cholinesterases inhibition, absorption, brain distribution, and toxicity

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F60162694%3AG44__%2F16%3A43875551" target="_blank" >RIV/60162694:G44__/16:43875551 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/62690094:18470/16:50004521 RIV/00216208:11150/16:10314133 RIV/00179906:_____/16:10314133

Výsledek na webu

<a href="http://dx.doi.org/10.1007/s12640-015-9582-4" target="_blank" >http://dx.doi.org/10.1007/s12640-015-9582-4</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1007/s12640-015-9582-4" target="_blank" >10.1007/s12640-015-9582-4</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Small quaternary inhibitors K298 and K524: cholinesterases inhibition, absorption, brain distribution, and toxicity

Popis výsledku v původním jazyce

Inhibitors of acetylcholinesterase (AChE) may be used in the treatment of various cholinergic deficits, among them being myasthenia gravis (MG). This paper describes the first in vivo data for promising small quaternary inhibitors (K298 and K524): acute toxicity study, cholinesterase inhibition, absorption, and blood-brain barrier penetration. The newly prepared AChE inhibitors (bis-quinolinium and quinolinium compounds) possess a positive charge in the molecule which ensures that anti-AChE action is restricted to peripheral effect. HPLC-MS was used for determination of real plasma and brain concentration in the pharmacokinetic part of the study, and standard non-compartmental analysis was performed. The maximum plasma concentrations were attained at 30 min (K298; 928.76 +/- A 115.20 ng/ml) and 39 min (K524; 812.40 +/- A 54.96 ng/ml) after i.m. application. Both compounds are in fact able to target the central nervous system. It seems that the difference in the CNS distribution profile depends on an active efflux system. The K524 brain concentration was actively decreased to below an effective level; in contrast, K298 progressively accumulated in brain tissue. Peripheral AChE inhibitors are still first-line treatment in the mild forms of MG. Commonly prescribed carbamates have many severe side effects related to AChE carbamylation. The search for new treatment strategies is still important. Unlike carbamates, these new compounds target AChE via apparent pi-pi or pi-cationic interaction aside at the AChE catalytic site.

Název v anglickém jazyce

Small quaternary inhibitors K298 and K524: cholinesterases inhibition, absorption, brain distribution, and toxicity

Popis výsledku anglicky

Inhibitors of acetylcholinesterase (AChE) may be used in the treatment of various cholinergic deficits, among them being myasthenia gravis (MG). This paper describes the first in vivo data for promising small quaternary inhibitors (K298 and K524): acute toxicity study, cholinesterase inhibition, absorption, and blood-brain barrier penetration. The newly prepared AChE inhibitors (bis-quinolinium and quinolinium compounds) possess a positive charge in the molecule which ensures that anti-AChE action is restricted to peripheral effect. HPLC-MS was used for determination of real plasma and brain concentration in the pharmacokinetic part of the study, and standard non-compartmental analysis was performed. The maximum plasma concentrations were attained at 30 min (K298; 928.76 +/- A 115.20 ng/ml) and 39 min (K524; 812.40 +/- A 54.96 ng/ml) after i.m. application. Both compounds are in fact able to target the central nervous system. It seems that the difference in the CNS distribution profile depends on an active efflux system. The K524 brain concentration was actively decreased to below an effective level; in contrast, K298 progressively accumulated in brain tissue. Peripheral AChE inhibitors are still first-line treatment in the mild forms of MG. Commonly prescribed carbamates have many severe side effects related to AChE carbamylation. The search for new treatment strategies is still important. Unlike carbamates, these new compounds target AChE via apparent pi-pi or pi-cationic interaction aside at the AChE catalytic site.

Druh

J_x - Nezařazeno - Článek v odborném periodiku (Jimp, Jsc a Jost)

CEP obor

FH - Neurologie, neurochirurgie, neurovědy

OECD FORD obor

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Projekt

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Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2016

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Neurotoxicity Research

ISSN

1029-8428

e-ISSN

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Svazek periodika

29

Číslo periodika v rámci svazku

2

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

8

Strana od-do

267-274

Kód UT WoS článku

000368194200008

EID výsledku v databázi Scopus

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