title: Pyranopyrazolotacrines as nonneurotoxic, Aβ-anti-aggregating and neuroprotective agents for Alzheimer's disease.
abstract: OBJECTIVE
  Due to the complex nature of Alzheimer's disease, there is a renewed search for multipotent, nonhepatotoxic tacrines.
  
  
  RESULTS
  This paper describes the synthesis and in vitro biological evaluation of eight new racemic 3-methyl-4-aryl-2,4,6,7,8,9-hexahydropyrazolo[4',3':5,6]pyrano[2,3-b]quinolin-5-amines (pyranopyrazolotacrines, PPT) as nonhepatotoxic multipotent tacrine analogs. Among these compounds, PPT4 is the less hepatotoxic in the cell viability assay on HepG2 cells, showing a good neuroprotective effect in the decreased cortical neuron viability induced by oligomycin A/rotenone analysis. PPT4 is a selective and good, noncompetitive EeAChE inhibitor, able to completely inhibit the Aβ1-40 aggregation induced by acetylcholinesterase.
  
  
  CONCLUSIONS
  A new family of nonhepatotoxic showing selective acetylcholinesterase inhibition, permeable tacrine analogs have been discovered for the potential treatment of Alzheimer's disease.
authors.affiliation: Laboratorio de Química Médica (IQOG, CSIC), C/Juan de la Cierva 3, 28006 Madrid, Spain.
authors.forename: Mourad
authors.initials: M
authors.lastname: Chioua
authors.affiliation: Departamento de Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Pérez-Peña
authors.affiliation: Departamento de Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: García-Font
authors.affiliation: Departamento de Química Orgánica y Química Inorgánica, Facultad de Biología, Ciencias Ambientales y Química, Universidad de Alcalá, Ctra. Barcelona, Km. 33.5, 28817 Alcalá de Henares, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Moraleda
authors.affiliation: Departamento de Química Orgánica y Química Inorgánica, Facultad de Biología, Ciencias Ambientales y Química, Universidad de Alcalá, Ctra. Barcelona, Km. 33.5, 28817 Alcalá de Henares, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Iriepa
authors.affiliation: SEPCO, (IQOG, CSIC), Juan de la Cierva, 3, 28006 Madrid, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Soriano
authors.affiliation: Laboratorio de Química Médica (IQOG, CSIC), C/Juan de la Cierva 3, 28006 Madrid, Spain.|Instituto Universitario de Investigación en Neuroquímica (IUIN), Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Marco-Contelles
authors.affiliation: Departamento de Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain.|Instituto Universitario de Investigación en Neuroquímica (IUIN), Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain.
authors.forename: María Jesús
authors.initials: MJ
authors.lastname: Oset-Gasque
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D000634:Aminoquinolines / Q000737:chemistry / Q000494:pharmacology*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D056945:Hep G2 Cells; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D009840:Oligomycins / Q000494:pharmacology; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000378:metabolism; D066329:Protein Aggregates / Q000187:drug effects; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology*; D012402:Rotenone / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000634:Aminoquinolines; D016229:Amyloid beta-Peptides; D006576:Heterocyclic Compounds, 4 or More Rings; D018696:Neuroprotective Agents; D009840:Oligomycins; D010446:Peptide Fragments; D066329:Protein Aggregates; D011720:Pyrazoles; C078592:amyloid beta-protein (1-40); D012402:Rotenone; C031004:oligomycin A; D000110:Acetylcholinesterase