Inserm, U 710, 34095 Montpellier, France.
J Psychopharmacol. 2011 Aug;25(8):1101-17. doi: 10.1177/0269881110379286. Epub 2010 Sep 9.
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.
四氢-N，N-二甲基-2，2-二苯基-3-呋喃甲胺盐酸盐（ANAVEX2-73）与毒蕈碱乙酰胆碱和 sigma(1)（σ(1)）受体具有亲和力，亲和力在低微摩尔范围内。我们在药理学和病理性健忘症模型中对其抗健忘症和神经保护潜力进行了表征。空间工作记忆通过 Y 迷宫中的自发交替和被动回避程序来评估非空间记忆。ANAVEX2-73（0.01-3.0 mg/kg 腹腔注射）减轻了东莨菪碱和地卓西平引起的学习障碍。ANAVEX2-73（300 µg/kg）还逆转了注射 Aβ（25-35）肽的小鼠的学习缺陷，Aβ（25-35）肽是一种非转基因阿尔茨海默病模型。当药物与 Aβ（25-35）同时注射时，在测试前 7 天，它阻止了学习障碍的出现。这种保护活性得到了证实，因为 ANAVEX2-73 阻断了海马中的 Aβ（25-35）诱导的氧化应激。这种作用对毒蕈碱受体拮抗剂东莨菪碱或 σ(1)蛋白拮抗剂 BD1047 的敏感性不同，证实了混合毒蕈碱/σ(1)药理学作用。最后，其独特的去甲基代谢物 ANAVEX19-144 也是有效的，并且 ANAVEX2-73 在 Aβ（25-35）之前 12 小时有效，其相关化合物 ANAVEX1-41 的作用时间更长。ANAVEX2-73 的神经保护活性、其混合胆碱能/σ(1)活性、其低有效剂量范围和长作用时间共同增强了其在阿尔茨海默病中的治疗潜力。
