Anti-amnesic and neuroprotective potentials of the mixed muscarinic receptor/sigma 1 (σ 1 ) 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.
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In preclinical studies, ANAVEX 2-73 showed significant results reverting cognitive impairment in AD mice models, suggesting anti-amnesic and neuroprotective action.
“In preclinical studies, ANAVEX 2-73 showed significant results reverting cognitive impairment in AD mice models, suggesting anti-amnesic and neuroprotective action [118].”
From Treatment of Alzheimer’s Disease: Beyond Symptomatic Therapies (2023) · cites this paper as [118]
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- Authors
- Villard, V., Espallergues, J., Keller, E., Vamvakides, A., & Maurice, T.
- Affiliations
- Inserm (FR)
- Anavex Life Sciences Corp. (United States) (US)
- ORCID
- Maurice, Tangui
- Venue
- Journal of Psychopharmacology
- Publisher
- SAGE Publications
- Published
- 2010-09-09
- Volume
- 25
- Issue
- 8
- Pages
- 1101-1117
- ISSN
- 0269-8811 (ISSN-L)
- 1461-7285
- OpenAlex
- W2143538247
- Cited by
- 139
- References
- 60
- Citations by year
- 2026: 9 · 2025: 8 · 2024: 9 · 2023: 15 · 2022: 9 · 2021: 13 · 2020: 13 · 2019: 13 · 2018: 5 · 2017: 11 · 2016: 4 · 2015: 10 · 2014: 8 · 2013: 3 · 2012: 5
- FWCI
- 1.56
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Psychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pharmacological Receptor Mechanisms and Effects
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Keywords
- muscarinic receptors, sigma-1 receptor, anti-amnesic effect, neuroprotection, Alzheimer's disease, amyloid beta 25-35, scopolamine-induced amnesia, spatial working memory, passive avoidance memory, oxidative stress, hippocampus, BD1047
- MeSH terms
- Alzheimer Disease, Animals, Avoidance Learning, Delayed-Action Preparations, Disease Models, Animal, Dose-Response Relationship, Drug, Furans, Hippocampus, Ligands, Male, Memory, Short-Term, Peptide Fragments, Protein Binding, Receptors, Muscarinic, Amyloid beta-Peptides, Receptors, sigma, Oxidative Stress, Neuroprotective Agents, Mice
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