UHPLC-HRMS study of anti-Alzheimer's drug candidates: metabolism of 7-MEOTA-tryptophan hybrids hampers their passage into brain
Abstract
Being among the top five causes of death in the developed world, Alzheimer's disease represents a majorsocio-economic issue. We administered a single intramuscular dose of two new hybrid anti-Alzheimer'scompounds, with 7-methoxytacrine (7-MEOTA; acetylcholinesterase inhibitor) and tryptophan (inhibitorof amyloid accumulation) in their structure, to rats.Using validated ultra-high-performance liquid chromatography coupled to high-resolution mass spec-trometry (UHPLC-HRMS) methods, we uncovered their inability to enter the site of action - the brain.
Wediscuss 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 atamide bond between tryptophan and the linker both in vitro and in vivo. Contrary to the parent compoundsthese metabolites - analogues of 7-MEOTA - can enter the brain in significant amounts.