PRO LEU GLY NH2 & DOPAMINE RECEPTOR MODULATION SAR STUDY

拟议研究的长期目标是获得更好的 对L-脯氨基-L-亮氨酰甘氨酰胺(PLG)作用方式的认识 调节中枢神经内多巴胺受体的敏感性 系统。为了追求这一目标，我们打算开展详细的 分析PLG的结构特征使该三肽能够 调节多巴胺受体的敏感性。 将合成一系列PLG的类似物，其中三个 该三肽的氨基酸残基将进行系统的修饰。一个 第二系列构象受限的PLG类似物将是 合成以获得关于生物活性的信息 该三肽的构象。 将测试PLG类似物与推定的 PLG受体使用放射配基结合分析。PLG类似物将 也要测试它们增强阿朴吗啡与多巴胺结合的能力 受体和拮抗抗精神病药物的特异性增强 ~3H-螺哌利多结合。最后，PLG类似物能够 对抗抗精神病药所致的过敏症也将被测量。 人们认为，拟议的研究不仅将为我们提供更好的 了解多巴胺受体的调制，但也会产生 潜在的药理工具，可以进一步帮助阐明 这一现象的机理。这反过来可能会带来更好的 对帕金森氏症等神经系统疾病的了解， 迟发性运动障碍、精神分裂症、抽动症和 阿片类药物耐受性和躯体依赖在中枢 多巴胺受体的敏感性也有牵连。

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.