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

PRO-亮氨酸-甘氨酸-NH2

• 批准号: 3400210
• 负责人: RODNEY L JOHNSON
• 金额: $ 12.49万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-12-01 至 1990-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3400210
• 关键词: Parkinson's disease; SCH 23390; Tourette's syndrome; apomorphine; catalepsy; centrally acting drug; chemical structure function; conformation; dopamine receptor; laboratory rat; lactams; neuropeptide receptor; oligopeptides; schizophrenia; tardive dyskinesia; tranquilizer; tritium

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.

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，希望能够解决分子问题 该三肽调节多巴胺受体的基础。 具体来说，PLG的亮氨酰残基将被L-和 D-N-Me-芳香族氨基酸残基，而未来的甘氨酰胺修饰 将以含硫和烯属氨基酸残基为中心。 包含噻唑烷-2-甲酰胺的 PLG 双环类似物 其结构内的δ-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什么方式 这种二酮哌嗪的结构类似于 PLG。 最后，类似物 PLG Pro-LeuOmega[E-CH=CH]Gly-NH2 的烯属类似物将是 为进一步探究其结构特征而合成 肽类似物，使其能够取代 3H-螺哌啶醇 结合位点并增强多巴胺激动剂与其结合 受体。 合成的 PLG 类似物将进行能力测试 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 能够从受体上取代 3H-PLG 并拮抗 氟哌啶醇诱导的多巴胺受体超敏性。 调节性 PLG 及其活性类似物对 D1-多巴胺受体的影响将是 使用特定的 D1 激动剂 SKF-38393 和 D1 拮抗剂进行研究 SCH-23390，PLG 可能的调节作用 激动剂诱导的多巴胺受体“下调”。 实验将 进行以确定 PLG 是否对 D1 和 D2 受体进行调节 通过 PLG 与鸟嘌呤核苷酸的相互作用介导 与这些相关的抑制性 (Gi) 蛋白的刺激性 (Gs) 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 为帕金森病、迟发性痴呆等疾病状态提供新的认识 运动障碍、精神分裂症和抽动秽语综合症 与多巴胺受体敏感性有关。