Weinstock M, Bejar C, Wang R H, Poltyrev T, Gross A, Finberg J P, Youdim M B
Department of Pharmacology, Hebrew University Hadassah School of Medicine, Ein Kerem, Jerusalem, Israel.
J Neural Transm Suppl. 2000(60):157-69. doi: 10.1007/978-3-7091-6301-6_10.
TV3326, [(N-propargyl-(3R) aminoindan-5-yl)-ethyl methyl carbamate] is a novel aminoindan derivative of the selective irreversible monoamine oxidase (MAO)-B inhibitor, rasagiline (N-propargyl-(1R)-aminoindan), possessing both cholinesterase (ChE) and MAO-inhibitory activity. In doses of 35-100 micromoles/kg administered orally to rats, it inhibits ChE by 25-40% and antagonises scopolamine-induced impairments in spatial memory. After daily administration of 75 micromoles/kg for 2 weeks, TV3326 does not show any motor stimulant effects but significantly reduces immobility in the forced swim test, an action consistent with that of known antidepressants. This could result from more than 70% inhibition of both MAO-A and B in the brain that occurs under these conditions, since it is not shared by the S-isomer, TV3279, which does not block MAO. TV3326 also shows selectivity for brain MAO, even after 2 months of daily administration, with little or no effect on the enzyme in the intestinal tract and liver. This reduces the likelihood of it producing the "cheese effect" if administered with tyramine-containing foods or beverages. TV3326 and TV3279 protect against ischemia-induced cytotoxicity in PC12 cells and reduce the oedema, deficits in motor function and memory after closed head injury in mice. These neuroprotective effects do not result from MAO inhibition. The pharmacological actions of TV3326 could be of clinical importance for the treatment of AD, and the drug is currently in development for this purpose.
TV3326，即[(N-炔丙基-(3R)-氨基茚满-5-基)-乙基甲基氨基甲酸酯]，是选择性不可逆单胺氧化酶(MAO)-B抑制剂雷沙吉兰（N-炔丙基-(1R)-氨基茚满）的一种新型氨基茚满衍生物，兼具胆碱酯酶(ChE)抑制活性和MAO抑制活性。以35 - 100微摩尔/千克的剂量口服给予大鼠时，它可抑制ChE达25% - 40%，并拮抗东莨菪碱诱导的空间记忆损伤。每日给予75微摩尔/千克，持续2周后，TV3326未表现出任何运动兴奋作用，但在强迫游泳试验中显著减少不动时间，这一作用与已知抗抑郁药一致。这可能是由于在此条件下大脑中MAO-A和B的抑制率超过70%，因为其S-异构体TV3279不具有此作用，TV3279不阻断MAO。即使每日给药2个月后，TV3326对脑MAO仍具有选择性，对肠道和肝脏中的该酶几乎没有影响。这降低了与含酪胺的食物或饮料一起服用时产生“奶酪效应”的可能性。TV3326和TV3279可保护PC12细胞免受缺血诱导的细胞毒性，并减轻小鼠闭合性颅脑损伤后的水肿、运动功能缺陷和记忆障碍。这些神经保护作用并非由MAO抑制引起。TV3326的药理作用对于阿尔茨海默病的治疗可能具有临床重要性，目前正在研发用于此目的的药物。
