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 acetylcholinesterase 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 IC(50) values in the subnanomolar and low nanomolar range, respectively.
Camps
Pelayo
P
Laboratori de Química Farmacèutica, Facultat de Farmàcia, Universitat de Barcelona, Av. Diagonal 643, E-08028, Barcelona, Spain. camps@ub.edu
Formosa
Xavier
X
Muñoz-Torrero
Diego
D
Petrignet
Julien
J
Badia
Albert
A
Clos
M Victoria
MV
D000110:Acetylcholinesterase / Q000737:chemistry*; D000634:Aminoquinolines / Q000138:chemical synthesis* / Q000737:chemistry; D000818:Animals; D001665:Binding Sites; D002091:Butyrylcholinesterase / Q000737:chemistry; D002417:Cattle; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D013329:Structure-Activity Relationship; D013619:Tacrine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry
D000634:Aminoquinolines; D002800:Cholinesterase Inhibitors; D006576:Heterocyclic Compounds, 4 or More Rings; C404518:huprine X; C404519:huprine Y; D013619:Tacrine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase