Synthesis and pharmacological evaluation of huprine-tacrine heterodimers:: Subnanomolar dual binding site acetylcholinesterase inhibitors

A series of huprine-tacrine heterodimers has been developed by connection of huprine Y, a compound with one of the highest affinities for the active site of acetyleholinesterase yet reported, with tacrine, a compound with known affinity for the peripheral site of the enzyme, through a linker of appropriate length to allow simultaneous interaction with both binding sites. These compounds exhibit human acetylcholinesterase and butyrylcholinesterase inhibitory activities with IC50 values in the subnanomolar and low nanomolar range, respectively.