Tejani-Butt S M, Hauptmann M, D'Mello A, Frazer A, Marcoccia J M, Brunswick D J
Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia.
Naunyn Schmiedebergs Arch Pharmacol. 1988 Nov;338(5):497-503. doi: 10.1007/BF00179320.
In this study, two ester pro-drugs of dopamine (DA) were synthesized and evaluated. These derivatives were the monobenzoyl (MBDA) and dibenzoyl (DBDA) esters of DA. MBDA was 300-fold and DBDA was 20,000-fold more lipophilic than DA itself. The half-lives of hydrolysis for MBDA and DBDA at physiologic pH and temperature were 15 and 420 min respectively. These compounds were radiolabelled and their uptake into brain measured. 14C-DBDA penetrated the brain rapidly; 0.28% of the dose injected was taken up per gram of brain tissue at 5 min. However DBDA did not produce measurable increases in DA levels in the brain. 14C-MBDA was found not to penetrate the brain. However, when MBDA was administered intracerebroventricularly (i.c.v.) to rats, it caused DOPAC levels to increase significantly both in the striatum and in the rest of the brain. The increase in the amount of DOPAC measured in the striatum was 3 to 10-fold greater than that seen in the rest of the brain. In rats that were pretreated with the MAO inhibitor, pargyline, MBDA given i.c.v. caused increases in DA levels in both the striatum and in the rest of the brain. The increased DA levels in striatum were considerably greater than those seen in the rest of the brain. From these results, it is inferred that MBDA is being hydrolyzed in vivo in the brain to form DA which is then taken up into dopaminergic neurons.(ABSTRACT TRUNCATED AT 250 WORDS)
在本研究中，合成并评估了多巴胺（DA）的两种酯前药。这些衍生物是DA的单苯甲酰（MBDA）和二苯甲酰（DBDA）酯。MBDA的亲脂性比DA本身高300倍，DBDA则高20000倍。MBDA和DBDA在生理pH和温度下的水解半衰期分别为15分钟和420分钟。这些化合物用放射性标记，并测定其在脑中的摄取情况。14C-DBDA迅速穿透大脑；在5分钟时，每克脑组织摄取了0.28%的注射剂量。然而，DBDA并未使脑中DA水平出现可测量的升高。发现14C-MBDA不能穿透大脑。然而，当向大鼠脑室内（i.c.v.）注射MBDA时，它使纹状体和脑的其他部位的3,4-二羟基苯乙酸（DOPAC）水平显著升高。纹状体中测得的DOPAC量的增加比脑的其他部位高3至10倍。在用单胺氧化酶（MAO）抑制剂帕吉林预处理的大鼠中，脑室内注射MBDA使纹状体和脑的其他部位的DA水平升高。纹状体中升高的DA水平比脑的其他部位显著更高。从这些结果可以推断，MBDA在脑内被体内水解形成DA，然后被摄取到多巴胺能神经元中。（摘要截断于250字）
