The neurotransmitter dopamine (DA) was covalently linked to oxazepam (OXA), a well-known positive allosteric modulator of γ-aminobutyric acid type-A (GABA_A) receptor, through a carbamate linkage (4) or a succinic spacer (6). These conjugates were synthesized with the aim of improving the delivery of DA into the brain and enhancing GABAergic transmission, which may be useful for the long-term treatment of Parkinson disease (PD). Structure-based permeability properties, in vitro stability, and blood–brain barrier (BBB) permeability studies led to identify the OXA–DA carbamate conjugate 4a as the compound better combining sufficient stability and ability to cross BBB. Finally, in vivo microdialysis experiments in freely moving rats demonstrated that 4a (20 mg/kg, i.p.) significantly increases extracellular DA levels into striatum, with a peak (more than 15-fold increase over the baseline) at about 80 min after a single administration. The stability and delivery data proved that 4a may be a promising candidate for further pharmacological studies in animal models of PD.

中文翻译：

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奥沙西m-多巴胺会增加完整大鼠纹状体中多巴胺的释放

神经递质多巴胺（DA）通过氨基甲酸酯键（4）或琥珀酸间隔基（6）与奥沙西m（OXA）共价连接，奥沙西（（OXA）是众所周知的A型γ-氨基丁酸（GABA _A）受体的正变构调节剂。。合成这些缀合物的目的是改善DA向大脑的传递并增强GABA能传递，这可能对帕金森病（PD）的长期治疗有用。基于结构的渗透性，体外稳定性和血脑屏障（BBB）渗透性研究确定OXA-DA氨基甲酸酯共轭物4a为更好地结合了足够的稳定性和穿越BBB的能力的化合物。最后，体内在自由移动的大鼠中进行的微透析实验表明，4a（20 mg / kg，ip）显着增加了纹状体中细胞外DA的水平，单次给药后约80分钟达到峰值（比基线增加15倍以上）。稳定性和递送数据证明4a可能是PD动物模型中进一步药理研究的有希望的候选者。