Qureshi A A, Abuirmeileh N, Burger W C, Din Z Z, Elson C E
Atherosclerosis. 1983 Feb;46(2):203-16. doi: 10.1016/0021-9150(83)90111-9.
AMO 1618 (2-isopropyl-4-dimethylamino-5-methylphenyl-1-piperidine carboxylate methyl chloride) was added to corn-soy based diets and fed to 9-week-old female chickens for 3 weeks to measure the inhibition of hepatic beta-hydroxy-beta-methylglutaryl coenzyme A (HMG-CoA) reductase and cholesterol 7 alpha-hydroxylase. Dose-related decreases in the activities of these two enzymes were obtained (2.5--15 ppm) of AMO 1618. Decreases in plasma total cholesterol, chol-HDL, and chol-LDL levels were observed, but the decreases in chol-LDL were substantially larger than those of chol-HDL in both chicken and rat. Assays of livers from rats fed 20 ppm AMO 1618 for 3 days had 24% less HMG-CoA reductase activity and 67% less cholesterol 7 alpha-hydroxylase activity than the controls. Plasma cholesterol in these animals was reduced 26%; the ratio of total cholesterol : chol-HDL was reduced from 3.27 to 2.67 and the chol-LDL : chol-HDL ratio was reduced from 1.96 to 1.14 as a result of the relatively brief treatment. Fatty acid synthetase (FAS) and other key lipogenic enzymes increased 1.5--4-fold in both the chicken and rat. The inhibition of HMG-CoA reductase and the induction of FAS by AMO 1618 were tested in vitro, using 10--100 micrograms (28--280 mumoles) for 15 min with isolated hepatocytes from chicken and rat. Linear responses in activity were dose-dependent and increased with duration of incubation (30 micrograms or 85 mumoles AMO 1618, 5--120 min) in both species. The results suggest the compound acts at the cellular level and AMO 1618 appears to possess several properties which recommend it for testing as a cholesterol-lowering agent in humans.
将AMO 1618（2-异丙基-4-二甲基氨基-5-甲基苯基-1-哌啶羧酸甲酯盐酸盐）添加到以玉米-大豆为基础的日粮中，喂食9周龄雌性鸡3周，以测定其对肝脏β-羟基-β-甲基戊二酰辅酶A（HMG-CoA）还原酶和胆固醇7α-羟化酶的抑制作用。在AMO 1618剂量为2.5至15 ppm时，这两种酶的活性出现了与剂量相关的下降。观察到血浆总胆固醇、胆固醇-HDL和胆固醇-LDL水平降低，但在鸡和大鼠中，胆固醇-LDL的降低幅度均显著大于胆固醇-HDL。给大鼠喂食20 ppm AMO 1618 3天，其肝脏检测结果显示，HMG-CoA还原酶活性比对照组低24%，胆固醇7α-羟化酶活性比对照组低67%。这些动物的血浆胆固醇降低了26%；由于治疗时间相对较短，总胆固醇与胆固醇-HDL的比值从3.27降至2.67，胆固醇-LDL与胆固醇-HDL的比值从1.96降至1.14。在鸡和大鼠中，脂肪酸合成酶（FAS）和其他关键的脂肪生成酶增加了1.5至4倍。使用10至100微克（28至280微摩尔）的AMO 1618，对鸡和大鼠的分离肝细胞进行15分钟的体外试验，以测试其对HMG-CoA还原酶的抑制作用和对FAS的诱导作用。两种动物的活性线性反应均呈剂量依赖性，并随孵育时间（30微克或85微摩尔AMO 1618，5至120分钟）的延长而增加。结果表明该化合物在细胞水平起作用，并且AMO 161看来具有多种特性，推荐将其作为人类降胆固醇药物进行测试。
