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

Publication date: Available online 24 May 2019Source: Journal of Pharmaceutical and Biomedical AnalysisAuthor(s): M. Mžik, J. Karasová-Žďárová, K. Chalupová, J Korábečný, V. Palička, V. ŠestákAbstractBeing 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.Extensive 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 using. Contrary to the parent compounds these metabolites – analogues of 7-MEOTA – can enter the brain in significant amounts.
Source: Journal of Pharmaceutical and Biomedical Analysis - Category: Drugs & Pharmacology Source Type: research