title: New multipotent tetracyclic tacrines with neuroprotective activity.
abstract: The synthesis and the biological evaluation (neuroprotection, voltage dependent calcium channel blockade, AChE/BuChE inhibitory activity and propidium binding) of new multipotent tetracyclic tacrine analogues (5-13) are described. Compounds 7, 8 and 11 showed a significant neuroprotective effect on neuroblastoma cells subjected to Ca(2+) overload or free radical induced toxicity. These compounds are modest AChE inhibitors [the best inhibitor (11) is 50-fold less potent than tacrine], but proved to be very selective, as for most of them no BuChE inhibition was observed. In addition, the propidium displacement experiments showed that these compounds bind AChE to the peripheral anionic site (PAS) of AChE and, consequently, are potential agents that can prevent the aggregation of beta-amyloid. Overall, compound 8 is a modest and selective AChE inhibitor, but an efficient neuroprotective agent against 70mM K(+) and 60microM H(2)O(2). Based on these results, some of these molecules can be considered as lead candidates for the further development of anti-Alzheimer drugs.
authors.affiliation: Laboratorio de Radicales Libres (IQOG, CSIC), C/Juan de la Cierva 3, 28006 Madrid, Spain. iqoc21@iqog.csic.es
authors.forename: José
authors.initials: J
authors.lastname: Marco-Contelles
authors.forename: Rafael
authors.initials: R
authors.lastname: León
authors.forename: Cristóbal
authors.initials: C
authors.lastname: de los Ríos
authors.forename: Antonio G
authors.initials: AG
authors.lastname: García
authors.forename: Manuela G
authors.initials: MG
authors.lastname: López
authors.forename: Mercedes
authors.initials: M
authors.lastname: Villarroya
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry; D002118:Calcium / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D015394:Molecular Structure; D009447:Neuroblastoma / Q000188:drug therapy / Q000473:pathology; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011419:Propidium / Q000378:metabolism; D013329:Structure-Activity Relationship; D013619:Tacrine / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects*
chemical_list: D002800:Cholinesterase Inhibitors; D018696:Neuroprotective Agents; D011419:Propidium; D013619:Tacrine; D007770:L-Lactate Dehydrogenase; D000110:Acetylcholinesterase; D002118:Calcium