title: Memantine-sulfur containing antioxidant conjugates as potential prodrugs to improve the treatment of Alzheimer's disease.
abstract: The approved treatments for Alzheimer's disease (AD) exploit mainly a symptomatic approach based on the use of cholinesterase inhibitors or N-methyl-D-aspartate (NMDA) receptor antagonists. Natural antioxidant compounds, able to pass through the blood-brain barrier (BBB), have been extensively studied as useful neuroprotective agents. A novel approach towards excitotoxicity protection and oxidative stress associated with excess β amyloid (Aβ) preservation in AD is represented by selective glutamatergic antagonists that possess as well antioxidant capabilities. In the present work, GSH (1) or (R)-α-lipoic acid (LA) (2) have been covalently linked with the NMDA receptor antagonists memantine (MEM). The new conjugates, proposed as potential antialzheimer drugs, should act both as glutamate receptor antagonists and radical scavenging agents. The physico-chemical properties and "in vitro" membrane permeability, the enzymatic and chemical stability, the demonstrated "in vitro" antioxidant activity associated to the capacity to inhibit Aβ(1-42) aggregation makes at least compound 2 a promising candidate for treatment of AD patients.
authors: Dipartimento di Farmacia, Università G. D'Annunzio, Via dei Vestini 31, 66100 Chieti, Italy.
authors: Piera
authors: P
authors: Sozio
authors: Laura S
authors: LS
authors: Cerasa
authors: Sara
authors: S
authors: Laserra
authors: Ivana
authors: I
authors: Cacciatore
authors: Catia
authors: C
authors: Cornacchia
authors: Ester S
authors: ES
authors: Di Filippo
authors: Stefania
authors: S
authors: Fulle
authors: Antonella
authors: A
authors: Fontana
authors: Antonello
authors: A
authors: Di Crescenzo
authors: Massimo
authors: M
authors: Grilli
authors: Mario
authors: M
authors: Marchi
authors: Antonio
authors: A
authors: Di Stefano
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy; D016229:Amyloid beta-Peptides / Q000737:chemistry; D000818:Animals; D000975:Antioxidants / Q000737:chemistry* / Q000494:pharmacology; D002460:Cell Line; D018691:Excitatory Amino Acid Antagonists / Q000737:chemistry* / Q000494:pharmacology; D005978:Glutathione / Q000737:chemistry* / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D008297:Male; D008559:Memantine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology; D008567:Membranes, Artificial; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry; D011355:Prodrugs / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000037:antagonists & inhibitors; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D008063:Thioctic Acid / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D000975:Antioxidants; D018691:Excitatory Amino Acid Antagonists; D008567:Membranes, Artificial; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D011355:Prodrugs; D017382:Reactive Oxygen Species; D016194:Receptors, N-Methyl-D-Aspartate; C075222:amyloid beta-protein (1-42); C000604149:lipoyl-memantine; D008063:Thioctic Acid; D005978:Glutathione; D008559:Memantine; D009638:Norepinephrine