Giannola L I, De Caro V, Giandalia G, Siragusa M G, Lamartina L
Dipartimento di Chimica e Tecnologie Farmaceutiche, Università di Palermo, Via Archirafi, 32, 90123 Palermo, Italy.
Pharmazie. 2008 Oct;63(10):704-10.
Dopamine delivery to the central nervous system (CNS) undergoes the permeability limitations of blood-brain barrier (BBB) which is a selective interface that excludes most water-soluble molecules from entering the brain. Neutral amino acids permeate the BBB by specific transport systems. Condensation of dopamine with neutral amino acids could afford potential prodrugs able to interact with the BBB endogenous transporters and easily enter the brain. The synthesis and characterization of the dopamine derivative 2-amino-N-[2-(3,4-dihydroxy-phenyl)-ethyl]-3-phenyl-propionamide (7) is described. The chemical and enzymatic stability of 7 was evaluated. The molecular weight (300 Da) and Log Papp (0.76) indicated that the physico-chemical characteristics of compound 7 are adequate to cross biological membranes. Compound 7 was enzymatically cleaved to free dopamine in rat brain homogenate (t1/2 = 460 min). In human plasma, the t1/2 of 7 was estimated comparable to that reported for L-DOPA. In view of a possible oral administration of 7, studies of its chemical behavior under conditions simulating those of the gastrointestinal tract showed that no dopamine production occurred; furthermore, 7 is able to permeate through a simulated intestinal mucosal membrane. The collected data suggest that compound 7 could beconsidered a very valuable candidate for subsequent in vivo evaluation.
多巴胺向中枢神经系统（CNS）的递送受到血脑屏障（BBB）通透性的限制，血脑屏障是一种选择性界面，可排除大多数水溶性分子进入大脑。中性氨基酸通过特定的转运系统透过血脑屏障。多巴胺与中性氨基酸的缩合可提供能够与血脑屏障内源性转运体相互作用并轻松进入大脑的潜在前药。本文描述了多巴胺衍生物2-氨基-N-[2-(3,4-二羟基苯基)-乙基]-3-苯基丙酰胺（7）的合成与表征。评估了7的化学稳定性和酶稳定性。分子量（300 Da）和Log Papp（0.76）表明化合物7的物理化学特性足以穿过生物膜。化合物7在大鼠脑匀浆中可被酶解为游离多巴胺（t1/2 = 460分钟）。在人血浆中，7的t1/2估计与左旋多巴报道的相当。鉴于7可能口服给药，在模拟胃肠道条件下对其化学行为的研究表明未产生多巴胺；此外，7能够透过模拟肠粘膜。收集的数据表明化合物7可被视为后续体内评估的非常有价值的候选物。
