title: Enzymatic and solid-phase synthesis of new donepezil-based L- and d-glutamic acid derivatives and their pharmacological evaluation in models related to Alzheimer's disease and cerebral ischemia.
abstract: Previously, we have described N-Bz-L-Glu[NH-2-(1-benzylpiperidin-4-yl)ethyl]-O-nHex (IQM9.21, L-1) as an interesting multifunctional neuroprotective compound for the potential treatment of neurodegenerative diseases. Here, we describe new derivatives and different synthetic routes, such as chemoenzymatic and solid-phase synthesis, aiming to improve the previously described route in solution. The lipase-catalysed amidation of L- and D-Glu diesters with N-benzyl-4-(2-aminoethyl)piperidine has been studied, using Candida antarctica and Mucor miehei lipases. In all cases, the α-amidated compound was obtained as the main product, pointing out that regioselectivity was independent of the reacting Glu enantiomer and the nature of the lipase. An efficient solid-phase route has been used to produce new donepezil-based L- and D-Glu derivatives, resulting in good yield. At micromolar concentrations, the new compounds inhibited human cholinesterases and protected neurons against toxic insults related to Alzheimer's disease and cerebral ischemia. The CNS-permeable compounds N-Cbz-L-Glu(OEt)-[NH-2-(1-benzylpiperidin-4-yl)ethyl] (L-3) and L-1 blocked the voltage-dependent calcium channels and L-3 protected rat hippocampal slices against oxygen-glucose deprivation, becoming promising anti-Alzheimer and anti-stroke lead compounds.
authors.affiliation: Instituto de Química Médica, Consejo Superior de Investigaciones Científicas (IQM-CSIC), C/ Juan de la Cierva 3, 28006, Madrid, Spain.
authors.forename: Leticia
authors.initials: L
authors.lastname: Monjas
authors.affiliation: Instituto de Química Médica, Consejo Superior de Investigaciones Científicas (IQM-CSIC), C/ Juan de la Cierva 3, 28006, Madrid, Spain.
authors.forename: Mariana P
authors.initials: MP
authors.lastname: Arce
authors.affiliation: Instituto Teófilo Hernando y Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, C/ Arzobispo Morcillo, 4, 28029, Madrid, Spain; Instituto de Investigación Sanitaria, Servicio de Farmacología Clínica, Hospital Universitario de la Princesa, 28006, Madrid, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: León
authors.affiliation: Instituto Teófilo Hernando y Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, C/ Arzobispo Morcillo, 4, 28029, Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Egea
authors.affiliation: Instituto de Química Médica, Consejo Superior de Investigaciones Científicas (IQM-CSIC), C/ Juan de la Cierva 3, 28006, Madrid, Spain.
authors.forename: Concepción
authors.initials: C
authors.lastname: Pérez
authors.affiliation: Instituto Teófilo Hernando y Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, C/ Arzobispo Morcillo, 4, 28029, Madrid, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Villarroya
authors.affiliation: Instituto Teófilo Hernando y Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, C/ Arzobispo Morcillo, 4, 28029, Madrid, Spain.
authors.forename: Manuela G
authors.initials: MG
authors.lastname: López
authors.affiliation: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CIB-CSIC), C/ Ramiro de Maeztu 9, 28040, Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Gil
authors.affiliation: Instituto de Química Médica, Consejo Superior de Investigaciones Científicas (IQM-CSIC), C/ Juan de la Cierva 3, 28006, Madrid, Spain.
authors.forename: Santiago
authors.initials: S
authors.lastname: Conde
authors.affiliation: Instituto de Química Médica, Consejo Superior de Investigaciones Científicas (IQM-CSIC), C/ Juan de la Cierva 3, 28006, Madrid, Spain. Electronic address: isabelrguez@iqm.csic.es.
authors.forename: María Isabel
authors.initials: MI
authors.lastname: Rodríguez-Franco
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy*; D002121:Calcium Channel Blockers / Q000737:chemistry / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D000077265:Donepezil; D005971:Glutamates / Q000737:chemistry / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects; D006801:Humans; D007189:Indans / Q000737:chemistry / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D060327:Solid-Phase Synthesis Techniques
chemical_list: D002121:Calcium Channel Blockers; D002800:Cholinesterase Inhibitors; D005971:Glutamates; D007189:Indans; D018696:Neuroprotective Agents; D010880:Piperidines; D000077265:Donepezil
keywords: Alzheimer's disease; Donepezil-based L- and D-Glu derivatives; Human cholinesterases; Mitochondrial oxidative stress; Neuroprotection; Stroke