title: Novel Levetiracetam Derivatives That Are Effective against the Alzheimer-like Phenotype in Mice: Synthesis, in Vitro, ex Vivo, and in Vivo Efficacy Studies.
abstract: We have synthesized a series of heptamethylene-linked levetiracetam-huprine and levetiracetam-(6-chloro)tacrine hybrids to hit amyloid, tau, and cholinergic pathologies as well as β-amyloid (Aβ)-induced epileptiform activity, some of the mechanisms that eventually lead to cognitive deficits in Alzheimer's disease patients. These hybrids are potent inhibitors of human acetylcholinesterase and butyrylcholinesterase in vitro and moderately potent Aβ42 and tau antiaggregating agents in a simple E. coli model of amyloid aggregation. Ex vivo determination of the brain acetylcholinesterase inhibitory activity of these compounds after intraperitoneal injection to C57BL6J mice has demonstrated their ability to enter the brain. The levetiracetam-huprine hybrid 10 significantly reduced the incidence of epileptic seizures, cortical amyloid burden, and neuroinflammation in APP/PS1 mice after a 4-week treatment with a 5 mg/kg dose. Moreover, the hybrid 10 rescued transgenic mice from cognitive deficits, thereby emerging as an interesting disease-modifying anti-Alzheimer drug candidate.
authors.affiliation: †Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institut de Biomedicina (IBUB), Universitat de Barcelona, Av. Joan XXIII 27-31, E-08028, Barcelona, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Sola
authors.affiliation: ‡Institut de Neuropatologia, Servei d'Anatomia Patològica, IDIBELL-Hospital Universitari de Bellvitge, Universitat de Barcelona, L'Hospitalet de Llobregat, 08908 Barcelona, Spain.|§CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto Carlos III, Spain.
authors.forename: Ester
authors.initials: E
authors.lastname: Aso
authors.affiliation: †Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institut de Biomedicina (IBUB), Universitat de Barcelona, Av. Joan XXIII 27-31, E-08028, Barcelona, Spain.
authors.forename: Daniela
authors.initials: D
authors.lastname: Frattini
authors.affiliation: ‡Institut de Neuropatologia, Servei d'Anatomia Patològica, IDIBELL-Hospital Universitari de Bellvitge, Universitat de Barcelona, L'Hospitalet de Llobregat, 08908 Barcelona, Spain.|§CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto Carlos III, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: López-González
authors.affiliation: ∥Departament de Fisicoquímica, Facultat de Farmàcia, and Institut de Nanociència i Nanotecnologia (IN2UB), Universitat de Barcelona, 08028 Barcelona, Spain.
authors.forename: Alba
authors.initials: A
authors.lastname: Espargaró
authors.affiliation: ∥Departament de Fisicoquímica, Facultat de Farmàcia, and Institut de Nanociència i Nanotecnologia (IN2UB), Universitat de Barcelona, 08028 Barcelona, Spain.
authors.forename: Raimon
authors.initials: R
authors.lastname: Sabaté
authors.affiliation: †Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institut de Biomedicina (IBUB), Universitat de Barcelona, Av. Joan XXIII 27-31, E-08028, Barcelona, Spain.
authors.forename: Ornella
authors.initials: O
authors.lastname: Di Pietro
authors.affiliation: ⊥Departament de Fisicoquímica, Facultat de Farmàcia (Campus Torribera), and IBUB, Universitat de Barcelona, Prat de la Riba 171, E-08921, Santa Coloma de Gramenet, Spain.
authors.forename: F Javier
authors.initials: FJ
authors.lastname: Luque
authors.affiliation: #Departament de Farmacologia, de Terapèutica, i de Toxicologia, Institut de Neurociències, Universitat Autònoma de Barcelona, E-08193, Bellaterra, Barcelona, Spain.
authors.forename: M Victòria
authors.initials: MV
authors.lastname: Clos
authors.affiliation: ‡Institut de Neuropatologia, Servei d'Anatomia Patològica, IDIBELL-Hospital Universitari de Bellvitge, Universitat de Barcelona, L'Hospitalet de Llobregat, 08908 Barcelona, Spain.|§CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto Carlos III, Spain.
authors.forename: Isidro
authors.initials: I
authors.lastname: Ferrer
authors.affiliation: †Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institut de Biomedicina (IBUB), Universitat de Barcelona, Av. Joan XXIII 27-31, E-08028, Barcelona, Spain.
authors.forename: Diego
authors.initials: D
authors.lastname: Muñoz-Torrero
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D066298:In Vitro Techniques; D000077287:Levetiracetam; D051379:Mice; D008810:Mice, Inbred C57BL; D018697:Nootropic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D010641:Phenotype; D010889:Piracetam / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D018697:Nootropic Agents; D000077287:Levetiracetam; D010889:Piracetam