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

这项研究的长期目标是更好地了解 Pro-Leu-Gly-NH 2（PLG）调节多巴胺受体的方式。 详细分析了结构/构象-活性关系， 我们的高效内酰胺类似物3（R）-（N-L-脯氨酰基）氨基-2-氧代-1- 吡咯烷乙酰胺（3）将进行，由此脯氨酰基残基和 内酰胺环被修饰，内酰胺环的3-位和内酰胺环的3-位被修饰， 分子的乙酰胺部分的α-碳被取代。 我们的高效双环噻唑烷内酰胺14的改性将 以及新的肽模拟物， 通过多个构象约束来限制角度， 合成了 将测试合成的化合物的能力， 增强多巴胺受体激动剂与D1和D2多巴胺的结合 使用牛尾状核、培养的细胞系或纯化的 制备D1和D2受体。 还将对类似物进行评价 因为它们能够从假定的PLG受体置换3 H-PLG。 将测试选定的类似物的拮抗能力， 氟哌啶醇（D2）和SCH 23390（D1）诱导的多巴胺受体 超敏反应，影响6-羟基多巴胺诱导的DA超敏反应， 并调节激动剂诱导的多巴胺受体下调。 放射自显影将用于研究PLG的相互作用 类似物与多巴胺在D1受体在不同水平的 纹状体 PLG及其类似物对D1和D2受体mRNA的影响 表达将被调查。 进一步调查 PLG与鸟嘌呤核苷酸的相互作用刺激或抑制 蛋白质将通过确定PLG及其 类似物：（a）多巴胺激动剂诱导的高亲和力刺激 （B）腺苷酸环化酶抑制/活化 （c）G蛋白（Gi、Gs和Go）水平及其与多巴胺受体激动剂的关系。 相应的mRNA水平。 这些研究应该为我们提供更好的 了解多巴胺受体调节，这反过来又会增加 我们对帕金森氏症、迟发性 运动障碍和精神分裂症，其中多巴胺受体敏感性的变化 被牵连了

The long term objective of this research is to gain a better understanding of the way in which Pro-Leu-Gly-NH2 (PLG) modulates dopamine receptors. Detailed analysis of the structure/conformation-activity relationships of our highly potent lactam analogue 3(R)-(N-L-prolyl)amino-2-oxo-1- pyrrolidineacetamide (3) will be carried out whereby the prolyl residue and lactam ring are modified and the 3-position of the lactam ring and the alpha-carbon of the acetamide portion of the molecule are substituted. Modifications of our highly effective bicyclic thiazolidine lactam 14 will be made and novel peptide mimics in which various phi and psi torsional angles are restricted through multiple conformational constraints will be synthesized. The compounds synthesized will be tested for their ability to enhance the binding of dopamine receptor agonists to D1- and D2-dopamine receptors using either bovine caudate, cultured cell lines, or purified preparations of D1- and D2-receptors. The analogues will also be evaluated for their ability to displace 3H-PLG from the putative PLG receptor. Selected analogues will be tested for their ability to antagonize haloperidol (D2)- and SCH 23390 (D1)-induced dopamine receptor supersensitivity, to affect 6-hydroxydopamine-induced DA supersensitivity, and to modulate agonist induced down-regulation of dopamine receptors. Autoradiography will be used to investigate the interaction of PLG analogues with dopamine at the D1 receptor at various levels of the striatum. The effect of PLG and its analogues on D1 and D2 receptor mRNA expression will be investigated. Further investigations into the interaction of PLG with the guanine nucleotide stimulatory or inhibitory proteins will be undertaken by determining the effect of PLG and its analogues on: (a) dopamine agonist-induced stimulation of high-affinity GTPase activity in membranes; (b) adenylate cyclase inhibition/activation by dopamine agonists; and (c) G-protein (Gi, Gs and Go) levels and their corresponding mRNA levels. These studies should provide us with a better understanding of dopamine receptor modulation which in turn should increase our understanding of such disease states as Parkinson's disease, tardive dyskinesia and schizophrenia where changes in dopamine receptor sensitivity have been implicated.