Characterisation of the anticholinesterase activity of two new tacrine-huperzine A hybrids.
The effects of two tacrine-huperzine A hybrids, (+/-)-huprine Y and (+/-)-huprine Z, have been evaluated. Bovine and human acetylcholinesterase (AChE) and human butyrylcholinesterase (BChE) inhibition were assayed by Ellman's method. The two huprines were more active than both tacrine and (-)-huperzine A as inhibitors of both human and bovine AChE, and they acted as mixed-type AChE inhibitors. Moreover, (+/-)-huprine Y exhibited a tight binding character seen in the experiments of reversibility of bovine AChE inhibitory activity. In addition, both compounds were more active toward AChE than toward BChE. Also, the selectivity for the human AChE was greater than for the bovine enzyme. In ex vivo studies performed in mice, both drugs showed a clear inhibitory activity of brain AChE, 20 min after i.p. injection, (+/-)-huprine Y being more potent than (+/-)-huprine Z [ID(50) 1.09 (0.39-2.98) vs. 5.77 (3.29-10.30) micromol/kg]. The time-course study of the inhibitory effect displayed a t(1/2) of 1 h for the two compounds. These results show that these drugs are two potent, central AChE inhibitors of potential interest in the treatment of AD.
Alcalá
Maria del Mar
Mdel M
Dpt de Farmacologia, de Terapèutica i de Toxicologia, Facultat de Medicina, Universitat Autònoma de Barcelona, 08193 Bellaterra (Barcelona), Spain.
Vivas
Nuria María
NM
Hospital
Susana
S
Camps
Pelayo
P
Muñoz-Torrero
Diego
D
Badia
Albert
A
D000470:Alkaloids; D000634:Aminoquinolines / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D002091:Butyrylcholinesterase / Q000737:chemistry; D002417:Cattle; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D012717:Sesquiterpenes / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013619:Tacrine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology
C476227:(+-)-huprine Z; D000470:Alkaloids; D000634:Aminoquinolines; D002800:Cholinesterase Inhibitors; D006576:Heterocyclic Compounds, 4 or More Rings; D012717:Sesquiterpenes; C404519:huprine Y; C050426:huperzine A; D013619:Tacrine; D002091:Butyrylcholinesterase