New tacrine-huperzine A hybrids (huprines):: Highly potent tight-binding acetylcholinesterase inhibitors of interest for the treatment of Alzheimer's disease

被引:193
作者
Camps, P
El Achab, R
Morral, J
Muñoz-Torrero, D
Badia, A
Baños, JE
Vivas, NM
Barril, X
Orozco, M
Luque, FJ
机构
[1] Univ Barcelona, Quim Farmaceut Lab, Fac Farm, E-08028 Barcelona, Spain
[2] Univ Barcelona, Dept Fis Quim, Fac Farm, E-08028 Barcelona, Spain
[3] Univ Autonoma Barcelona, Fac Med, Dept Farmacol & Terapeut, Barcelona 08193, Spain
[4] Univ Barcelona, Fac Quim, Dept Bioquim, E-08028 Barcelona, Spain
关键词
D O I
10.1021/jm000980y
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Several new 12-amino-6,7, 10,11-tetrahydro-7, 11-methanocycloocta[b]quinoline derivatives (tacrine-huperzine A hybrids, huprines) have been synthesized and tested as acetylcholinesterase (AChE) inhibitors. All of the new compounds contain either a methyl or ethyl group at position 9 and one or two (chloro, fluoro, or methyl) substituents at positions 1, 2, or 3. Among the monosubstituted derivatives, the more active are those substituted at position 3, their activity following the order 3-chloro > 3-fluoro > 3-methyl > 3-hydrogen. For the 1,3-difluoro and 1,3-dimethyl derivatives, the effect of the substituents is roughly additive. No significant differences were observed for the inhibitory activity of 9-methyl vs B-ethyl derivatives mono-or disubstituted at positions 1 and/or 3. The levorotatory enantiomers of these hybrid compounds are much more active (eutomers) than the dextrorotatory forms (distomers) as AChE inhibitors. Compounds rac-20, (-)-20, rac-26, (-)-26, rac-30, (-)-30, and rac-31 showed human AChE inhibitory activities up to 28.5-fold higher than for the corresponding bovine enzyme. Also, rac-19, (-)-20, (-)-30, and rac-31 were very selective for human AChE vs butyrylcholinesterase (BChE), the AChE inhibitory activities being 438-871-fold higher than for BChE. Several hybrid compounds, specially (-)-20 and (-)-30, exhibited tight-binding character, showing higher activity after incubation of the enzyme with the inhibitor than without incubation, though the reversible nature of the enzyme-inhibitor interaction was demonstrated by dialysis. The results of the ox vivo experiments also supported the tight-binding character of compounds (-)-20 and (-)-30 and showed their ability to cross the blood-brain barrier. Molecular modeling simulations of the AChE-inhibitor complex provided a basis to explain the differences in inhibitory activity of these compounds.
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页码:4657 / 4666
页数:10
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