Tetracyclic nitrogen bridgehead compounds, dibenzodiazecines and tricyclic quinazolinimines, in which the size of the alicyclic ring system and the length of the alkyl chain between the quinazolinimine moiety and a phenyl ring connected to the imine nitrogen atom were changed systematically, were synthesized and their ability to inhibit acetyl- and butyrylcholinesterase (AChE/BChE), respectively, was evaluated. Moderate and strong inhibitors of BChE--compared to galanthamine and rivastigmine--were identified, which show mixed affinities or are moderately or highly selective towards BChE, respectively.
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Probing the mid-gorge of cholinesterases with spacer-modified bivalent quinazolinimines leads to highly potent and selective butyrylcholinesterase inhibitors.
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School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK.
The spacer structure of homobivalent quinazolinimes acting as potent acetyl-(AChE)- and butyrylcholinesterase (BChE) inhibitors was chemically modified introducing tertiary amine and acyl-amide moieties, and the activities at both ChEs were evaluated. Molecular docking was applied to explain the data and probe the capacity of the mid-gorge site of both ChEs. The novel spacer structures considerably alter the biological profile of bivalent quinazolinimines with regard to both inhibitory activity and selectivity.
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Institute of Pharmacology and Toxicology, Friedrich Schiller University Jena, Jena, Germany.
Tricyclic quinazolinimines as a novel class of potent inhibitors of cholinesterases in vitro are micro- and sub-micromolar inhibitors with activities at both acetyl- (AChE) and butyrylcholinesterase (BChE) or at BChE only. To further establish the antiamnesic properties of this class of compounds, an in vivo test system has been established. Cognitive impairment in rats was reversibly induced by scopolamine (0.
View Article and Find Full Text PDFNovel tricyclic quinazolinimines and related tetracyclic nitrogen bridgehead compounds as cholinesterase inhibitors with selectivity towards butyrylcholinesterase.
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Lehrstuhl für Pharmazeutische/Medizinische Chemie, Institut für Pharmazie, Friedrich-Schiller-Universität Jena, Philosophenweg 14, D-07743 Jena, Germany.
Tetracyclic nitrogen bridgehead compounds, dibenzodiazecines and tricyclic quinazolinimines, in which the size of the alicyclic ring system and the length of the alkyl chain between the quinazolinimine moiety and a phenyl ring connected to the imine nitrogen atom were changed systematically, were synthesized and their ability to inhibit acetyl- and butyrylcholinesterase (AChE/BChE), respectively, was evaluated. Moderate and strong inhibitors of BChE--compared to galanthamine and rivastigmine--were identified, which show mixed affinities or are moderately or highly selective towards BChE, respectively.
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