title: Characterisation of the anticholinesterase activity of two new tacrine-huperzine A hybrids.
abstract: 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.
authors.affiliation: Dpt de Farmacologia, de Terapèutica i de Toxicologia, Facultat de Medicina, Universitat Autònoma de Barcelona, 08193 Bellaterra (Barcelona), Spain.
authors.forename: Maria del Mar
authors.initials: Mdel M
authors.lastname: Alcalá
authors.forename: Nuria María
authors.initials: NM
authors.lastname: Vivas
authors.forename: Susana
authors.initials: S
authors.lastname: Hospital
authors.forename: Pelayo
authors.initials: P
authors.lastname: Camps
authors.forename: Diego
authors.initials: D
authors.lastname: Muñoz-Torrero
authors.forename: Albert
authors.initials: A
authors.lastname: Badia
mesh_terms: 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
chemical_list: 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