PRO-LEU-GLY-NH2 AND DOPAMINE RECEPTOR MODULATION

PRO-LEU-GLY-NH2 和多巴胺受体调节

• 批准号: 2263753
• 负责人: RODNEY L JOHNSON
• 金额: $ 18.7万
• 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 1995-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2263753
• 关键词: 6 hydroxydopamine; G protein; Parkinson's disease; SCH 23390; X ray crystallography; adenylate cyclase; autoradiography; central nervous system stimulants; chemical structure function; chemical synthesis; conformation; corpus striatum; disease /disorder model; dopamine agonists; dopamine receptor; drug screening /evaluation; gene expression; guanosinetriphosphatases; haloperidol; laboratory rat; lactams; membrane activity; messenger RNA; molecular dynamics; neuropeptide receptor; nuclear magnetic resonance spectroscopy; nucleic acid probes; peptide analog; peptide chemical synthesis; peptides; receptor binding; receptor expression; receptor sensitivity; second messengers; tardive dyskinesia; tissue /cell culture; tritium

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.

这项研究的长期目标是获得更好的理解 Pro-Leu-Gly-Gly-NH2（PLG）调节多巴胺受体的方式。 对结构/构象活性关系的详细分析 我们高度有效的LACTAM类似物3（R） - （N-L-丙酰）氨基-2-oxo-1- 将进行吡咯烷二酸（3） 乳糖环修饰，乳酸环的3位和 取代了分子的乙酰胺部分的α-碳。 修改我们高效的双环噻唑烷莱酰胺14将 被制成和新颖的肽模拟物，其中各种PHI和PSI扭转 角度通过多个构象约束受到限制 合成。 合成的化合物的能力将进行测试 增强多巴胺受体激动剂与D1-和D2-多巴胺的结合 使用牛尾状的受体，培养的细胞系或纯化的受体 D1和D2受体的制剂。 类似物也将评估 因为它们能够从推定的PLG受体中取代3H-PLG。 选定的类似物将测试其对抗的能力 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超敏性， 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 与多巴胺在D1受体处类似于不同水平的 纹状体。 PLG及其类似物对D1和D2受体mRNA的影响 表达将被研究。 进一步调查 PLG与鸟嘌呤核苷酸刺激或抑制作用的相互作用 蛋白质将通过确定PLG及其效果来进行蛋白质 类似于：（a）多巴胺激动剂引起的高亲和力刺激 膜中的GTPase活性； （b）腺苷酸环化酶抑制/激活 多巴胺激动剂； （c）G蛋白（GI，GS和GO）及其 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，反过来应该增加 我们对诸如帕金森氏病，迟到等疾病状态的理解 多巴胺受体敏感性变化的运动障碍和精神分裂症 已被牵连。