Anti-amnesic and neuroprotective potentials of the mixed muscarinic receptor/sigma1 (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) (sigma(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 mu g/kg) also reversed the learning deficits in mice injected with A beta(25-35) peptide, a non-transgenic Alzheimer's disease model. When the drug was injected simultaneously with A beta(25-35), 7 days before the tests, it blocked the appearance of learning impairments. This protective activity was confirmed since ANAVEX2-73 blocked the A beta(25-35)-induced oxidative stress in the hippocampus. This effect was differentially sensitive to the muscarinic receptor antagonist scopolamine or the sigma(1) protein antagonist BD1047, confirming the mixed muscarinic/sigma(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 A beta(25-35), than its related compound ANAVEX1-41. The neuroprotective activity of ANAVEX2-73, its mixed cholinergic/sigma(1) activity, its low active dose range and its long duration of action together reinforce its therapeutic potential in Alzheimer's disease.