PRO LEU GLY NH2 & DOPAMINE RECEPTOR MODULATION SAR STUDY

前亮氨酸甘氨酸NH2

• 批准号: 3400207
• 负责人: RODNEY L JOHNSON
• 金额: $ 10.1万
• 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 1986-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3400207
• 关键词: Parkinson's disease; Tourette's syndrome; apomorphine; catalepsy; centrally acting drug; chemical structure function; conformation; lactams; oligopeptides; schizophrenia; tardive dyskinesia; tranquilizer

The long term objective of the proposed research is to gain a better understanding of the way in which L-Prolyl-L-Leucylglycinamide (PLG) modulates the sensitivity of dopamine receptors within the central nervous system. In pursuit of this objective, we intend to carry out a detailed analysis of the structural features of PLG that enable this tripeptide to modulate dopamine receptor sensitivity. A series of analogues of PLG will be synthesized wherein each of the three amino acid residues of this tripeptide will be systematically modified. A second series of conformationally constrained analogues of PLG will be synthesized in order to obtain information about the biologically active conformation of this tripeptide. The PLG analogues will be tested for their ability to bind to the putative PLG receptor using a radioligand binding assay. The PLG analogues will also be tested for their ability to enhance apomorphine binding to dopamine receptors and to antagonize neuroleptic drug enhancement of specific 3H-spiroperidol binding. Finally, the ability of the PLG analogues to antagonize neuroleptic drug-induced catalepsy will also be measured. It is felt that the proposed study will not only provide us with a better understanding of dopamine receptor modulation, but will also yield potential pharmacological tools which could further help elucidate the mechanism of the phenomenon. This in turn may lead to a better understanding of neurological disorders such as Parkinson's Disease, tardive dyskinesia, schizophrenia, Gilles de la Tourette syndrome, and opiate tolerance and physical dependence in which changes in central dopamine receptor sensitivity have been implicated.

拟议研究的长期目标是获得更好的结果 了解 L-Prolyl-L-Leucylglycinamide (PLG) 的合成方式 调节中枢神经内多巴胺受体的敏感性 系统。 为了实现这一目标，我们打算进行详细的 分析 PLG 的结构特征，使该三肽能够 调节多巴胺受体敏感性。 将合成一系列 PLG 类似物，其中三种 该三肽的氨基酸残基将被系统地修饰。 一个 第二系列的 PLG 构象受限类似物将是 合成以获得有关生物活性的信息 该三肽的构象。 PLG 类似物将测试其与假定的结合能力 使用放射性配体结合测定的 PLG 受体。 PLG类似物将 还测试了它们增强阿扑吗啡与多巴胺结合的能力 受体并拮抗精神安定药物增强的特异性 3H-螺哌啶醇结合。 最后，PLG 类似物的能力 拮抗精神安定药物引起的僵直症也将被测量。 我们认为，拟议的研究不仅将为我们提供更好的 了解多巴胺受体调节，但也会产生 潜在的药理学工具可以进一步帮助阐明 现象的机制。 这反过来可能会带来更好的结果 了解帕金森病等神经系统疾病， 迟发性运动障碍、精神分裂症、抽动秽语综合征和 阿片类药物耐受性和身体依赖性，其中中枢神经系统发生变化 多巴胺受体敏感性已被牵连。