Small Quaternary Inhibitors K298 and K524: Cholinesterases Inhibition, Absorption, Brain Distribution, and Toxicity
Jazyk angličtina Země Spojené státy americké Médium print-electronic
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
26646154
DOI
10.1007/s12640-015-9582-4
PII: 10.1007/s12640-015-9582-4
Knihovny.cz E-zdroje
- Klíčová slova
- Acetylcholinesterase, Blood–brain barrier, Myasthenia gravis, Preclinical study, Small quaternary inhibitors,
- MeSH
- chinolinové sloučeniny aplikace a dávkování krev farmakokinetika toxicita MeSH
- cholinesterasové inhibitory aplikace a dávkování krev farmakokinetika toxicita MeSH
- cholinesterasy krev MeSH
- hematoencefalická bariéra účinky léků metabolismus MeSH
- krysa rodu Rattus MeSH
- LD50 MeSH
- mozek - chemie účinky léků MeSH
- mozek účinky léků metabolismus MeSH
- potkani Wistar MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- chinolinové sloučeniny MeSH
- cholinesterasové inhibitory MeSH
- cholinesterasy MeSH
UNLABELLED: 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 ± 115.20 ng/ml) and 39 min (K524; 812.40 ± 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 π-π or π-cationic interaction aside at the AChE catalytic site.
Biomedical Research Center University Hospital Hradec Kralove Czech Republic
Department of Medical Biochemistry Faculty of Medicine Hradec Kralove Czech Republic
Zobrazit více v PubMed
J Biol Chem. 2003 Oct 3;278(40):38948-55 PubMed
J Pharmacokinet Pharmacodyn. 2013 Jun;40(3):369-76 PubMed
Med Res Rev. 2013 Jan;33(1):139-89 PubMed
Curr Treat Options Neurol. 2013 Apr;15(2):224-39 PubMed
Clin Exp Immunol. 2014 Mar;175(3):408-18 PubMed
J Anat. 2014 Jan;224(1):29-35 PubMed
Eur J Clin Pharmacol. 1992;42(4):371-4 PubMed
Curr Opin Neurol. 2012 Oct;25(5):523-9 PubMed
Neurotox Res. 2013 Jan;23(1):63-8 PubMed
Clin Chim Acta. 1999 Oct;288(1-2):73-90 PubMed
Bioorg Med Chem Lett. 2011 Apr 15;21(8):2505-9 PubMed
Eur J Med Chem. 2011 Feb;46(2):811-8 PubMed
Ann Neurol. 2010 Dec;68(6):776-7 PubMed
J Med Chem. 2011 Apr 28;54(8):2627-45 PubMed
Behav Brain Res. 2009 Nov 5;203(2):207-14 PubMed
J Enzyme Inhib Med Chem. 2011 Apr;26(2):245-53 PubMed
Eur J Drug Metab Pharmacokinet. 1991 Oct-Dec;16(4):299-303 PubMed
Mini Rev Med Chem. 2011 Mar;11(3):247-62 PubMed
J Vet Emerg Crit Care (San Antonio). 2011 Oct;21(5):547-51 PubMed
