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 sigma₁ (σ₁) 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 σ₁ protein antagonist BD1047, confirming the mixed muscarinic/σ₁ 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/σ₁ activity, its low active dose range and its long duration of action together reinforce its therapeutic potential in Alzheimer’s disease.