PRO LEU GLY NH2 & DOPAMINE RECEPTOR MODULATION SAR STUDY

拟议研究的长期目标是获得更好的 了解L-脯氨酰-L-亮氨酰甘氨酰胺（PLG） 调节中枢神经系统内多巴胺受体的敏感性 系统 为了实现这一目标，我们打算开展一项详细的 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PLG的一系列类似物，其中三种类似物中的每一种均 该三肽的氨基酸残基将被系统地修饰。 一 第二系列的构象约束类似物的PLG将是 为了获得关于生物活性的信息， 这三种肽的构象。 将测试PLG类似物与推定的受体结合的能力。 使用放射性配体结合测定的PLG受体。 PLG类似物将 也可以测试它们增强阿扑吗啡与多巴胺结合的能力 受体和拮抗神经安定药物增强的特异性 3 H-螺哌啶结合。 最后，PLG类似物的能力， 还将测量拮抗神经安定药物诱导的僵住症。 据认为，拟议的研究不仅将为我们提供一个更好的 了解多巴胺受体调节，但也将产生 潜在的药理学工具，可以进一步帮助阐明 现象的机制。 这反过来可能会导致更好的 对神经系统疾病如帕金森病的理解， 迟发性运动障碍、精神分裂症、抽动秽语综合征，以及 阿片类药物耐受性和身体依赖性的变化， 多巴胺受体敏感性也有牵连。

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.