Synthesis and evaluation of tacrine-huperzine A hybrids as acetylcholinesterase inhibitors of potential interest for the treatment of Alzheimer's disease.
Seventeen polycyclic compounds related to tacrine and huperzine A have been prepared as racemic mixtures and tested as acetylcholinesterase (AChE) inhibitors. The conjunctive pharmacomodulation of huperzine A (carbobicyclic substructure) and tacrine (4-aminoquinoline substructure) led to compound 7jy, 2.5 times less active than tacrine as AChE inhibitor, but much more active than its (Z)-stereoisomer (7iy). Derivatives 7dy and 7ey, lacking the ethylidene substituent, showed to be more active than tacrine. Many other structural modifications of 7jy led to less active compounds. Compounds 7dy and 7ey also showed to be much more active than tacrine in reversing the partial neuromuscular blockade induced by d-tubocurarine.
Badia
A
A
Departament de Farmacologia i Terapèutica, Facultat de Medicina, Universitat Autònoma de Barcelona, Spain.
Baños
J E
JE
Camps
P
P
Contreras
J
J
Görbig
D M
DM
Muñoz-Torrero
D
D
Simón
M
M
Vivas
N M
NM
D000110:Acetylcholinesterase / Q000378:metabolism*; D000470:Alkaloids; D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D002417:Cattle; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009469:Neuromuscular Junction / Q000187:drug effects; D018696:Neuroprotective Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D012717:Sesquiterpenes / Q000737:chemistry* / Q000494:pharmacology; D013055:Spectrophotometry, Infrared; D013619:Tacrine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
D000470:Alkaloids; D002800:Cholinesterase Inhibitors; D018696:Neuroprotective Agents; D012717:Sesquiterpenes; C050426:huperzine A; D013619:Tacrine; D000110:Acetylcholinesterase