• Je něco špatně v tomto záznamu ?

UHPLC-HRMS study of anti-Alzheimer's drug candidates: metabolism of 7-MEOTA-tryptophan hybrids hampers their passage into brain

M. Mžik, J. Žďárová-Karasová, K. Chalupová, J. Korábečný, V. Palička, V. Šesták,

. 2019 ; 174 (-) : 134-144. [pub] 20190524

Jazyk angličtina Země Velká Británie

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc20006284

Being among the top five causes of death in the developed world, Alzheimer's disease represents a major socio-economic issue. We administered a single intramuscular dose of two new hybrid anti-Alzheimer's compounds, with 7-methoxytacrine (7-MEOTA; acetylcholinesterase inhibitor) and tryptophan (inhibitor of amyloid accumulation) in their structure, to rats. Using validated ultra-high-performance liquid chromatography coupled to high-resolution mass spectrometry (UHPLC-HRMS) methods, we uncovered their inability to enter the site of action - the brain. We discuss four possible explanations: i) physico-chemical properties, ii) lack of active/facilitated transport, iii) effective efflux and/or iv) extensive metabolism. High-resolution mass spectrometric analyses proved that the compounds are easily hydrolysed at amide bond between tryptophan and the linker both in vitro and in vivo. Contrary to the parent compounds these metabolites - analogues of 7-MEOTA - can enter the brain in significant amounts.

Citace poskytuje Crossref.org

000      
00000naa a2200000 a 4500
001      
bmc20006284
003      
CZ-PrNML
005      
20210726074905.0
007      
ta
008      
200511s2019 xxk f 000 0|eng||
009      
AR
024    7_
$a 10.1016/j.jpba.2019.05.051 $2 doi
035    __
$a (PubMed)31167157
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a xxk
100    1_
$a Mžik, Martin $u Department of Clinical Biochemistry and Diagnostics, University Hospital and Faculty of Medicine Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic. $7 xx0262461
245    10
$a UHPLC-HRMS study of anti-Alzheimer's drug candidates: metabolism of 7-MEOTA-tryptophan hybrids hampers their passage into brain / $c M. Mžik, J. Žďárová-Karasová, K. Chalupová, J. Korábečný, V. Palička, V. Šesták,
520    9_
$a Being among the top five causes of death in the developed world, Alzheimer's disease represents a major socio-economic issue. We administered a single intramuscular dose of two new hybrid anti-Alzheimer's compounds, with 7-methoxytacrine (7-MEOTA; acetylcholinesterase inhibitor) and tryptophan (inhibitor of amyloid accumulation) in their structure, to rats. Using validated ultra-high-performance liquid chromatography coupled to high-resolution mass spectrometry (UHPLC-HRMS) methods, we uncovered their inability to enter the site of action - the brain. We discuss four possible explanations: i) physico-chemical properties, ii) lack of active/facilitated transport, iii) effective efflux and/or iv) extensive metabolism. High-resolution mass spectrometric analyses proved that the compounds are easily hydrolysed at amide bond between tryptophan and the linker both in vitro and in vivo. Contrary to the parent compounds these metabolites - analogues of 7-MEOTA - can enter the brain in significant amounts.
650    _2
$a Alzheimerova nemoc $7 D000544
650    _2
$a zvířata $7 D000818
650    _2
$a hematoencefalická bariéra $7 D001812
650    _2
$a mozek $x metabolismus $7 D001921
650    _2
$a cholinesterasové inhibitory $x farmakokinetika $7 D002800
650    _2
$a vysokoúčinná kapalinová chromatografie $7 D002851
650    _2
$a hydrolýza $7 D006868
650    _2
$a mužské pohlaví $7 D008297
650    _2
$a krysa rodu Rattus $7 D051381
650    _2
$a potkani Wistar $7 D017208
650    _2
$a takrin $x analogy a deriváty $x farmakokinetika $7 D013619
650    _2
$a tandemová hmotnostní spektrometrie $7 D053719
650    _2
$a tryptofan $x farmakokinetika $7 D014364
655    _2
$a časopisecké články $7 D016428
700    1_
$a Žďárová-Karasová, J $u Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Hradec Kralove, Czech Republic; Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic.
700    1_
$a Chalupová, K $u Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic; Department of Chemistry, Faculty of Science, University of Hradec Kralove, Rokitanskeho 62, 500 03 Hradec Kralove, Czech Republic.
700    1_
$a Korábečný, J $u Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Hradec Kralove, Czech Republic; Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic.
700    1_
$a Palička, V $u Department of Clinical Biochemistry and Diagnostics, University Hospital and Faculty of Medicine Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic.
700    1_
$a Šesták, V $u Department of Clinical Biochemistry and Diagnostics, University Hospital and Faculty of Medicine Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic. Electronic address: vit.sestak@fnhk.cz.
773    0_
$w MED00002894 $t Journal of pharmaceutical and biomedical analysis $x 1873-264X $g Roč. 174, č. - (2019), s. 134-144
856    41
$u https://pubmed.ncbi.nlm.nih.gov/31167157 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y a $z 0
990    __
$a 20200511 $b ABA008
991    __
$a 20210726074811 $b ABA008
999    __
$a ok $b bmc $g 1525142 $s 1096340
BAS    __
$a 3
BAS    __
$a PreBMC
BMC    __
$a 2019 $b 174 $c - $d 134-144 $e 20190524 $i 1873-264X $m Journal of pharmaceutical and biomedical analysis $n J Pharm Biomed Anal $x MED00002894
LZP    __
$a Pubmed-20200511

Najít záznam

Citační ukazatele

Možnosti archivace