PRO-LEU-GLY-NH2 & DOPAMINE RECEPTOR MODULATION STUDY

这项研究的长期目标是更好地了解 L-脯氨基-L-亮氨酰甘氨酰胺(PLG)三肽的作用途径 调节多巴胺受体。为了实现这一目标，我们打算 继续我们对结构-活性关系的详细分析 PLG，并开始研究，有望解决分子 这是该三肽调节多巴胺受体的基础。 具体地说，PLG的亮氨酸残基将由L取代--和 D-N-Me-芳香族氨基酸残基，而未来的甘氨酰胺修饰 将以含硫和烯烃氨基酸残基为中心。 含有噻唑烷-2-甲酰胺的PLG的双环类似物 而三角洲-内酰胺类药物在其结构内的残留也将进行检测。 将合成环(亮氨酸)的类似物，以确定以何种方式 这种二酮基哌嗪在结构上类似于PLG。最后，类似于 PLG Pro-LeuOmega[E-CH=CH]Gly-NH2的烯烃类似物将是 为了进一步探索这一结构特征， 使其能够取代~3H-螺哌利多的肽类似物 以及增强多巴胺激动剂与其 受体。合成的PLG类似物将被测试它们的能力 增强多巴胺激动剂ADTN和NPA与多巴胺的结合 感受器。具有高活性的类似物将被评估其 将~3H-PLG从其受体上置换并拮抗的能力 氟哌啶醇诱导的多巴胺受体超敏反应。调整性 PLG及其活性类似物对D1-多巴胺受体的影响 D_1受体激动剂SKF-38393和D_1受体拮抗剂的研究 SCH-23390，以及PLG可能的调控作用 激动剂诱导多巴胺受体“下调”。实验将会 以确定PLG对D_1和D_2受体的调节 是通过PLG与鸟嘌呤核苷酸的相互作用而介导的 刺激(Gs)与这些相关的抑制(GI)蛋白 感受器。最后，将尝试开发一种更好的放射性配体 用于PLG受体结合试验。这些研究应该为我们提供一个 更好地理解多巴胺受体的调制，这反过来可能 为帕金森氏症、迟缓等疾病状态提供新的线索 运动障碍、精神分裂症和抽动障碍综合征 在多巴胺受体敏感性方面也有牵连。

The long-term objective of this research is to gain a better understanding of the way in which the tripeptide L-prolyl-L-leucylglycinamide (PLG) modulates dopamine receptors. In pursuit of this objective, we intend to continue our detailed analysis of the structure-activity relationships of PLG and also to begin studies that hopefully will address the molecular basis for this tripeptide's modulation of dopamine receptors. Specifically, the leucyl residue of PLG will be replaced with L- and D-N-Me-aromatic amino acid residues, while future glycinamide modifications will center around sulfur-containing and olefinic amino acid residues. Bicyclic analogues of PLG that incorporate the thiazolidine-2-carboxamide and Delta-lactam residues within their structure will also be carried out. Analogues of cyclo(leu-gly) will be synthesized to determine in what manner this diketopiperazine resembles PLG in structure. Finally, analogues of the olefinic analogue of PLG Pro-LeuOmega[E-CH=CH]Gly-NH2 will be synthesized in order to explore further the structural features of this peptide analogue that enable it to displace 3H-spiroperidol from its binding sites as well as enhance the binding of dopamine agonists to their receptor. The PLG analogues synthesized will be tested for their ability to enhance the binding of the dopamine agonists ADTN and NPA to dopamine receptors. Analogues with high activity will be evaluated for their ability to displace 3H-PLG from its receptors and to antagonize haloperidol-induced dopamine receptor supersensitivity. The modulatory effects of PLG and its active analogues on D1-dopamine receptors will be investigated using the specific D1-agonist SKF-38393 and D1-antagonist SCH-23390, as will the possible modulatory effect of PLG on agonist-induced "down regulation" of dopamine receptors. Experiments will be conducted to determine whether PLG's modulation of D1- and D2-receptors is mediated through the interaction of PLG with the guanine nucleotide stimulatory (Gs) on inhibitory (Gi) proteins that are associated with these receptors. Finally, attempts will be made to develop a better radioligand for the PLG-receptor binding assay. These studies should provide us with a better understanding of dopamine receptor modulation, which in turn may shed new light on disease states such as Parkinson's Disease, tardive dyskinesia, schizophrenia, and Gilles de la Tourette syndrome where changes in dopamine receptor sensitivity have been implicated.