Inhibitors of the
enzyme acetylcholinesterase (AChE) slow and sometimes reverse the
cognitive decline experienced by individuals with
Alzheimer's disease.
Huperzine A, a
natural product used in traditional Chinese herbal medicine, and
tacrine (
Cognex) are among the potent AChE inhibitors used in this treatment, but the search for more selective inhibitors continues. We report herein the synthesis and characterization of (-)-12-amino-3-chloro-9-ethyl-6,7, 10,11-tetrahydro-7,11-methanocycloocta[b]
quinoline hydrochloride (
huprine X), a hybrid that combines the carbobicyclic substructure of
huperzine A with the
4-aminoquinoline substructure of
tacrine.
Huprine X inhibited human AChE with an inhibition constant K(I) of 26 pM, indicating that it binds to this
enzyme with one of the highest affinities yet reported. Under equivalent assay conditions, this affinity was 180 times that of
huperzine A, 1200 times that of
tacrine, and 40 times that of
E2020 (
donepezil,
Aricept), the most selective AChE inhibitor currently approved for
therapeutic use. The association and dissociation rate constants for
huprine X with AChE were determined, and the location of its binding site on the
enzyme was probed in competition studies with the peripheral site inhibitor
propidium and the acylation site inhibitor
edrophonium.
Huprine X showed no detectable affinity for the
edrophonium-AChE complex. In contrast,
huprine X did form a ternary complex with
propidium and AChE, although its affinity for the free
enzyme was found to be 17 times its affinity for the
propidium-AChE complex. These data indicated that
huprine X binds to the
enzyme acylation site in the active site gorge but interferes slightly with the binding of peripheral site
ligands.