The dopamine-amino acid conjugate DA-Phen was firstly designed to obtain a useful prodrug for the therapy of Parkinson's disease, but experimental evidence shows that it effectively interacts with D₁ dopamine receptors (D₁DRs), leading to an enhancement in cognitive flexibility and to the development of adaptive strategies in aversive mazes, together with a decrease in despair-like behavior. In this paper, homology modelling, molecular dynamics, and site mapping of D1 receptor were carried out with the aim of further performing docking studies on other dopamine conjugates compared with D1 agonists, in the attempt to identify new compounds with potential dopaminergic activity. Two new conjugates (DA-Trp 2C, and DA-Leu 3C) have been identified as the most promising candidates, and consequently synthesized. Preliminary evaluation in terms of distribution coefficient (D^pH7.4), stability in rat brain homogenate, and in human plasma confirmed that DA-Trp (2C), and DA-Leu (3C) could be considered as very valuable candidates for further in vivo studies as new dopaminergic drugs.

中文翻译：

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设计，合成和初步评估多巴胺-氨基酸共轭物作为潜在的D1多巴胺能调节剂

多巴胺-氨基酸共轭物DA-Phen最初是为了获得治疗帕金森氏病的有用前药而设计的，但实验证据表明，它与D ₁多巴胺受体有效相互作用（D ₁DR（DR），从而导致认知灵活性的增强和厌恶迷宫中自适应策略的发展，以及绝望感类似行为的减少。在本文中，进行了D1受体的同源性建模，分子动力学和位点定位，目的是与D1激动剂相比，进一步对其他多巴胺结合物进行对接研究，以试图鉴定具有潜在多巴胺能活性的新化合物。两种新的结合物（DA-Trp 2C和DA-Leu 3C）已被确定为最有前途的候选物，因此被合成。初步评估分配系数（D ^pH7.4）），大鼠脑匀浆和人血浆中的稳定性证实，DA-Trp（2C）和DA-Leu（3C）可以作为新的多巴胺能药物被认为是用于进一步体内研究的非常有价值的候选药物。