den Daas I, de Boer P, Tepper P G, Rollema H, Horn A S
Department of Medicinal Chemistry, University Centre for Pharmacy, Groningen, The Netherlands.
J Pharm Pharmacol. 1991 Jan;43(1):11-6. doi: 10.1111/j.2042-7158.1991.tb05439.x.
The in-vivo activities of eight carbamate prodrugs of the D2-agonist N-0437 were determined by examining the effects of the prodrugs, after their oral administration in rats with unilateral 6-OHDA lesions of the striatum. The resulting contralateral turning was used as an index of the activity of the compounds. A comparison of the area under the curve of the time-effect curves of the prodrugs, revealed a significantly improved duration of action compared with N-0437 during the period 11-15 h after administration, for the propylcarbamate and the dimethoxyphenylcarbamate derivatives. The 2,4-dimethylphenylcarbamate showed a significantly enhanced turning behaviour over the whole 15 h time interval in comparison with N-0437. Three of the nine carbamates were virtually unhydrolysed in rat serum at 37 degrees C, while the other test compounds were hydrolysed relatively slowly, with t1/2 values ranging from 1.5-6 h. The test compounds differed greatly in partition coefficients, which were estimated by RP-HPLC (1-12 times more lipophilic than N-0437). The potential cholinesterase inhibiting properties of the carbamate prodrugs were assessed by a simple in-vitro incubation assay, which showed that only two carbamates were very weak cholinesterase inhibitors.
通过在单侧纹状体6-羟基多巴胺损伤的大鼠口服给药后，检测8种D2激动剂N-0437的氨基甲酸酯前药的体内活性。所产生的对侧旋转被用作化合物活性的指标。前药时间-效应曲线的曲线下面积比较显示，与N-0437相比，丙基氨基甲酸酯和二甲氧基苯基氨基甲酸酯衍生物在给药后11至15小时期间的作用持续时间显著改善。与N-0437相比，2,4-二甲基苯基氨基甲酸酯在整个15小时时间间隔内显示出显著增强的旋转行为。9种氨基甲酸酯中的3种在37℃的大鼠血清中几乎不被水解，而其他测试化合物水解相对较慢，t1/2值范围为1.5至6小时。测试化合物的分配系数差异很大，通过反相高效液相色谱法估计（比N-0437亲脂性高1至12倍）。通过简单的体外孵育试验评估氨基甲酸酯前药的潜在胆碱酯酶抑制特性，结果表明只有两种氨基甲酸酯是非常弱的胆碱酯酶抑制剂。
