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

这项研究的长期目标是更好地了解 三肽L-脯氨酰-L-亮氨酰甘氨酰胺（PLG） 调节多巴胺受体。 为达致这个目标，我们打算 继续详细分析的结构-活性关系 PLG，并开始研究，希望将解决分子 三肽调节多巴胺受体的基础。 具体地，PLG的亮氨酰基残基将被L-取代， D-N-Me-芳香族氨基酸残基，而未来的甘氨酰胺修饰 将以含硫和烯属氨基酸残基为中心。 掺入噻唑烷-2-甲酰胺的PLG的双环类似物 并且其结构内的Delta-内酰胺残基也将被进行。 环（亮氨酸-甘氨酸）的类似物将被合成，以确定以何种方式 该二酮哌嗪在结构上类似于PLG。 最后， PLG Pro-LeuOmega[E-CH=CH] Gly-NH 2烯烃类似物将是 合成，以进一步探索这种结构特征， 肽类似物，使其能够取代3 H-螺哌啶从其 结合位点以及增强多巴胺激动剂与它们的 受体的 将测试合成的PLG类似物的能力， 为了增强多巴胺激动剂ADTN和NPA与多巴胺的结合， 受体。 将评估具有高活性的类似物的 从其受体置换3 H-PLG并拮抗 氟哌啶醇诱导的多巴胺受体超敏反应。 述调节性 PLG及其活性类似物对D1-多巴胺受体的影响将被 使用特异性D1激动剂SKF-38393和D1拮抗剂进行研究 SCH-23390，以及PLG对 激动剂诱导的多巴胺受体“下调”。 实验将 进行以确定PLG是否调节D1和D2受体 通过PLG与鸟嘌呤核苷酸的相互作用介导 刺激性（Gs）对抑制性（Gi）蛋白的作用， 受体。 最后，将尝试开发更好的放射性配体 用于PLG-受体结合测定。 这些研究应该为我们提供一个 更好地了解多巴胺受体调节，这反过来可能 为帕金森氏症、迟发性痴呆、 运动障碍、精神分裂症和抽动秽语综合征， 与多巴胺受体敏感性有关。

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.