Weinstock M, Gorodetsky E, Wang R H, Gross A, Weinreb O, Youdim M B H
Department of Pharmacology, Hebrew University, Hadassah Medical Centre, Ein Kerem, Jerusalem, Israel.
Neuropharmacology. 2002 Nov;43(6):999-1005. doi: 10.1016/s0028-3908(02)00176-4.
TV-3326 is a novel cholinesterase inhibitor that produces irreversible brain-selective inhibition of monoamine oxidase (MAO)-A and B and has antidepressant-like activity in rats after chronic oral administration. This study determined whether TV-3326 would cause less potentiation than other irreversible MAO-inhibitors of the blood pressure (BP) response to oral tyramine in conscious rabbits. Dose-response curves were established for the increase in BP induced by tyramine (5-200 mg/kg) administered orally via a naso-pharyngeal tube. From these, the dose that increased BP by 30 mmHg (ED(30)) was computed for each rabbit before and after oral administration of clorgyline, 1 mg/kg for one week, tranylcypromine 10 mg/kg, once, moclobemide, 20 mg/kg 3 times and TV-3326, 26 mg/kg for 2 weeks. Clorgyline, tranylcypromine and TV-3326 inhibited brain MAO-A by 90%; the former two inhibited intestinal MAO-A by 85-97% but TV-3326 had no effect. Tranylcypromine and clorgyline produced 6 and 20-fold increases in the pressor response to tyramine while TV-3326, like moclobemide, only potentiated it 2-fold. If TV-3326 is found to produce as little potentiation of the tyramine response in human subjects, it may be a potentially useful therapeutic agent for the treatment of Alzheimer's disease with depression.
TV-3326是一种新型胆碱酯酶抑制剂，可对单胺氧化酶（MAO）-A和B产生不可逆的脑选择性抑制作用，慢性口服给药后在大鼠中具有抗抑郁样活性。本研究确定了与其他不可逆MAO抑制剂相比，TV-3326对清醒家兔口服酪胺后血压（BP）反应的增强作用是否更小。通过鼻饲管口服给予酪胺（5-200mg/kg），建立血压升高的剂量反应曲线。据此，计算每只家兔在口服氯吉兰（1mg/kg，持续一周）、反苯环丙胺（10mg/kg，单次）、吗氯贝胺（20mg/kg，3次）和TV-3326（26mg/kg，持续2周）前后，使血压升高30mmHg的剂量（ED(30)）。氯吉兰、反苯环丙胺和TV-3326对脑MAO-A的抑制率为90%；前两者对肠道MAO-A的抑制率为85-97%，但TV-3326无此作用。反苯环丙胺和氯吉兰使对酪胺的升压反应分别增加6倍和20倍，而TV-3326与吗氯贝胺一样，仅使其增强2倍。如果发现TV-3326对人类受试者酪胺反应的增强作用同样很小，那么它可能是治疗伴有抑郁症的阿尔茨海默病的一种潜在有用的治疗药物。
