Pop E, Anderson W, Prókai-Tátrai K, Brewster M E, Fregly M, Bodor N
College of Pharmacy, University of Florida, J. Hillis Miller Health Center, Gainesville 32610.
J Med Chem. 1990 Aug;33(8):2216-21. doi: 10.1021/jm00170a028.
The essential amino acid, tryptophan, has been shown to lower blood pressure in rats when administered orally or intravenously. In order to potentially enhance this action, a brain-targeting chemical delivery system (CDS) approach was applied to this compound. The CDS is based on a dihydropyridine----pyridinium ion redox system, chemically analogous to the naturally occurring NADH----NAD+ system. The dihydropyridine moiety containing carrier is chemically attached to the amino group by an amide-type bonding while the carboxylic acid functionality is esterified to various alcohols. Physicochemical studies of the new derivatives were performed. The determined chromatographic Rm values indicate an increased lipophilicity for the CDSs compared to the parent compound. Oxidation stability studies performed on selected compounds using a ferricyanide-mediated method showed that the CDSs are oxidized to the respective quaternary salt forms. Activity studies performed in deoxycorticosterone acetate induced hypertensive rats, demonstrated that the delivery system for tryptophan reduced blood pressure more efficiently for a longer time than did the parent compound.
必需氨基酸色氨酸经口服或静脉给药后已被证明可降低大鼠血压。为了潜在地增强这种作用，一种脑靶向化学递送系统（CDS）方法被应用于该化合物。该CDS基于二氢吡啶 - 吡啶鎓离子氧化还原系统，在化学上类似于天然存在的NADH - NAD + 系统。含二氢吡啶部分的载体通过酰胺型键化学连接到氨基上，而羧酸官能团则被酯化为各种醇类。对新衍生物进行了物理化学研究。所测定的色谱Rm值表明，与母体化合物相比，CDS的亲脂性增加。使用铁氰化物介导的方法对选定化合物进行的氧化稳定性研究表明，CDS被氧化为各自的季盐形式。在醋酸脱氧皮质酮诱导的高血压大鼠中进行的活性研究表明，色氨酸递送系统比母体化合物更有效地降低血压，且作用时间更长。
