Anti-amnesic and neuroprotective potentials of the mixed muscarinic receptor/sigma 1 (σ1) ligand ANAVEX2-73, a novel aminotetrahydrofuran derivative.

Abstract

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.

• Authors: Vanessa Villard, Julie Espallergues, Emeline Keller, Alexandre Vamvakides, Tangui Maurice
• Journal: Journal of psychopharmacology (Oxford, England) (J Psychopharmacol) Vol. 25 Issue 8 Pg. 1101-17 (Aug 2011) ISSN: 1461-7285 [Electronic] United States
• PMID: 20829307 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• Delayed-Action Preparations
• Furans
• Ligands
• Neuroprotective Agents
• Peptide Fragments
• Receptors, Muscarinic
• Receptors, sigma
• amyloid beta-protein (25-35)
• tetrahydro-N, N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride
• tetrahydro-N, N-dimethyl-5,5-diphenyl-3-furanmethanamine hydrochloride

Topics

• Alzheimer Disease (drug therapy, physiopathology)
• Amyloid beta-Peptides (toxicity)
• Animals
• Avoidance Learning
• Delayed-Action Preparations (administration & dosage, metabolism, pharmacology)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Furans (metabolism, pharmacology)
• Hippocampus (drug effects, pathology)
• Ligands
• Male
• Memory, Short-Term (drug effects)
• Mice
• Neuroprotective Agents (administration & dosage, metabolism, pharmacology)
• Oxidative Stress (drug effects)
• Peptide Fragments (toxicity)
• Protein Binding
• Receptors, Muscarinic (metabolism)
• Receptors, sigma (metabolism)