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

Several new 12-amino-6,7, 10,11-tetrahydro-7, 11-methanocycloocta[b]quinoli ne derivatives (tacrine-huperzine A hybrids, huprines) have been synthesize d and tested as acetylcholinesterase (AChE) inhibitors. All of the new comp ounds 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 posit ion 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 o f the substituents is roughly additive. No significant differences were obs erved for the inhibitory activity of 9-methyl vs B-ethyl derivatives mono-o r disubstituted at positions 1 and/or 3. The levorotatory enantiomers of th ese hybrid compounds are much more active (eutomers) than the dextrorotator y forms (distomers) as AChE inhibitors. Compounds rac-20, (-)-20, rac-26, ( -)-26, rac-30, (-)-30, and rac-31 showed human AChE inhibitory activities u p to 28.5-fold higher than for the corresponding bovine enzyme. Also, rac-1 9, (-)-20, (-)-30, and rac-31 were very selective for human AChE vs butyryl cholinesterase (BChE), the AChE inhibitory activities being 438-871-fold hi gher 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 rever sible nature of the enzyme-inhibitor interaction was demonstrated by dialys is. 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-inhibi tor complex provided a basis to explain the differences in inhibitory activ ity of these compounds.