Synthesis, in vitro pharmacology, and molecular modeling of very potent tacrine-huperzine A hybrids as acetylcholinesterase inhibitors of potential interest for the treatment of Alzheimer's disease

Eleven new 12-amino-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinoline derivatives [tacrine (THA)-huperzine A hybrids, rac-21-31] have been synthe sized as racemic mixtures and tested as acetylcholinesterase (AChE) inhibit ors. For derivatives unsubstituted at the benzene ring, the highest activit y was obtained for the g-ethyl. derivative rac-20, previously prepared by o ur group. More bulky substituents at position 9 led to less active compound s, although some of them [9-isopropyl (rac-22), 9-allyl (rac-23), and 9-phe nyl (rac-26)] show activities similar to that of THA. Substitution at posit ion 1 or 3 with methyl or fluorine atoms always led to more active compound s. Among them, the highest activity was observed for the 3-fluoro-9-methyl derivative rac-28 [about 15-fold more active than THA and about 9-fold more active than (-)-huperzine A]. The activity of some THA-huperzine A hybrids (rac-19, rac-20, rac-28, and rac-30), which were separated into their enan tiomers by chiral medium-pressure liquid chromatography (chiral MPLC), usin g microcrystalline cellulose triacetate as the chiral stationary phase, sho wed the eutomer to be always the levorotatory enantiomer, their activity be ing roughly double that of the corresponding racemic mixture, the distomer being much less active. Also, the activity of some of these compounds inhib iting butyrylcholinesterase (BChE) was tested. Most of them [rac-27-31, (-) -28, and (-)-30], which are more active than (-)-huperzine A as AChE inhibi tors, turned out to be quite selective for AChE, although not so selective as (-)-huperzine A. Most of the tested compounds 19-31 proved to be much mo re active than THA in reversing the neuromuscular blockade induced by d-tub ocurarine. Molecular modeling of the interaction of these compounds with AC hE from Torpedo californica showed them to interact as truly THA-huperzine A hybrids: the 4-aminoquinoline subunit of (-)-19 occupies the same positio n of the corresponding subunit in THA, while its bicyclo[3.3.1]nonadiene su bstructure roughly occupies the same position of the corresponding substruc ture in (-)-huperzine A, in agreement with the absolute configurations of(- )-19 and (-)-huperzine A.