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-NH2(PLG)调节多巴胺受体的方式。 详细分析了其结构/构象-活性关系 我们的高效内酰胺类似物3(R)-(N-L-丙氨基)氨基-2-氧代-1- 将进行吡咯烷基乙酰胺(3)，从而使Pro残基和 对内酰胺环进行了改性，内酰胺环和内酰胺环的3位 分子中乙酰胺部分的α-碳被取代。 我们高效的双环噻唑烷内酰胺14的修饰将 制备新型多肽模拟物，其中各种phi和psi扭转 角度是通过多个构象约束来限制的 合成的。合成的化合物将被测试它们的能力 增强多巴胺受体激动剂与D_1和D_2-多巴胺的结合 使用牛尾状、培养的细胞系或纯化的受体 D_1和D_2受体的制备。还将对类似物进行评估 因为它们有能力取代可能的PLG受体上的~3H-PLG。 选定的类似物将被测试其拮抗能力 氟哌啶醇(D2)和SCH 23390(D1)诱导的多巴胺受体 超敏反应，影响6-羟基多巴胺诱导的多巴胺超敏反应， 并调节激动剂诱导的多巴胺受体下调。 放射自显影将被用来研究PLG的相互作用 与多巴胺在不同水平的D1R的类似物 纹状体。白藜芦醇及其类似物对D_1、D_2受体基因表达的影响 表达将被调查。对该事件的进一步调查 PLG与鸟嘌呤核苷酸的相互作用 蛋白质将通过确定PLG和它的作用 类似物：(A)多巴胺激动剂诱导的高亲和力刺激 膜上GTP酶活性；(B)腺苷环化酶抑制/激活 多巴胺激动剂；和(C)G蛋白(Gi、Gs和Go)水平及其 相应的mRNA水平。这些研究应该为我们提供更好的 对多巴胺受体调制的理解，这反过来应该增加 我们对帕金森氏症、迟缓等疾病状态的理解 运动障碍和精神分裂症，多巴胺受体敏感性的变化 都有牵连。

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.