Anti amnesic and neuroprotective potentials of the mixed muscarinic receptor/sigma1 (s1) ligand ANAVEX2 73, a novel aminotetrahydrofuran derivative
Tetrahydro N, N dimethyl 2, 2 diphenyl 3 furanmethanamine hydrochloride (ANAVEX2 73) binds to muscarinic acetylcholine and sigma1 (s1) 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 ug/kg) also reversed the learning deficits in mice injected with Ab25 35 peptide, a non transgenic Alzheimer's disease model. When the drug was injected simultaneously with Ab25 35, 7 days before the tests, it blocked the appearance of learning impairments. This protective activity was confirmed since ANAVEX2 73 blocked the Ab25 35 induced oxidative stress in the hippocampus. This effect was differentially sensitive to the muscarinic receptor antagonist scopolamine or the s1 protein antagonist BD1047, confirming the mixed muscarinic/s1 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 Ab25 35, than its related compound ANAVEX1 41. The neuroprotective activity of ANAVEX2 73, its mixed cholinergic/s1 activity, its low active dose range and its long duration of action together reinforce its therapeutic potential in Alzheimer's disease.
Journal of psychopharmacology