Anti-amnesic and neuroprotective potentials of the mixed muscarinic receptor/sigma 1 (σ1) ligand ANAVEX2-73, a novel aminotetrahydrofuran derivative.
Tetrahydro-N, N-dimethyl-2, 2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73) binds to muscarinic acetylcholine and sigma(1) (σ(1)) receptors with affinities in the low micromolar range. We characterized its anti-amnesic and neuroprotective potentials in pharmacological and pathological amnesia models. Spatial working memory was evaluated using spontaneous alternation in the Y-maze and non-spatial memory using passive avoidance procedures. ANAVEX2-73 (0.01-3.0 mg/kg i.p.) alleviated the scopolamine- and dizocilpine-induced learning impairments. ANAVEX2-73 (300 µg/kg) also reversed the learning deficits in mice injected with Aβ(25-35) peptide, a non-transgenic Alzheimer's disease model. When the drug was injected simultaneously with Aβ(25-35), 7 days before the tests, it blocked the appearance of learning impairments. This protective activity was confirmed since ANAVEX2-73 blocked the Aβ(25-35)-induced oxidative stress in the hippocampus. This effect was differentially sensitive to the muscarinic receptor antagonist scopolamine or the σ(1) protein antagonist BD1047, confirming the mixed muscarinic/σ(1) pharmacological action. Finally, its unique demethyl metabolite, ANAVEX19-144, was also effective and ANAVEX2-73 presented a longer duration of action, effective 12 h before Aβ(25-35), than its related compound ANAVEX1-41. The neuroprotective activity of ANAVEX2-73, its mixed cholinergic/σ(1) activity, its low active dose range and its long duration of action together reinforce its therapeutic potential in Alzheimer's disease.
Villard
Vanessa
V
Inserm, U 710, 34095 Montpellier, France.
Espallergues
Julie
J
Keller
Emeline
E
Vamvakides
Alexandre
A
Maurice
Tangui
T
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000633:toxicity; D000818:Animals; D001362:Avoidance Learning; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005663:Furans / Q000378:metabolism / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D008024:Ligands; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects; D051379:Mice; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D010446:Peptide Fragments / Q000633:toxicity; D011485:Protein Binding; D011976:Receptors, Muscarinic / Q000378:metabolism*; D017480:Receptors, sigma / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D003692:Delayed-Action Preparations; D005663:Furans; D008024:Ligands; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D011976:Receptors, Muscarinic; D017480:Receptors, sigma; C074636:amyloid beta-protein (25-35); C568535:tetrahydro-N, N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride; C525028:tetrahydro-N, N-dimethyl-5,5-diphenyl-3-furanmethanamine hydrochloride