Pilot--Molecular features of cembranoids as nicotinic a

中试--烟碱类西松烷内酯的分子特征

• 批准号: 7120465
• 负责人: VESNA Ana ETEROVIC
• 金额: --
• 依托单位: UNIVERSIDAD CENTRAL DEL CARIBE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-07 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7120465
• 关键词: Torpedo; affinity labeling; analog; biological products; cell line; coral; diterpenes; drug design /synthesis /production; drug screening /evaluation; fish electric organ; high performance liquid chromatography; inhibitor /antagonist; nicotine; nicotinic receptors; radiotracer; receptor binding; tobacco

Tobacco leaves contain both an agonist, nicotine, and various antagonists of nicotinic acetylcholine receptors. The last group is composed of cyclic diterpenoids called cembranoids. Preliminary evidence suggests that these compounds may accumulate in the brain to a concentration sufficient to significantly modify nicotine action. Cembranoid nicotinic antagonists are also found in marine invertebrates, namely gorgonian corals. These organisms display a stunning variety of cembrane derivatives, presenting an ideal opportunity for structure-activity relationship studies. The goals of this proposal are: 1. To determine the molecular features of the cembranoid molecule that affect its affinity for the nAChR from electric organ. For that purpose, synthetic analogues of the most abundant active marine cembranoid, pseudoplexauric acid methyl ester (PAME), will be prepared by organic synthesis and tested for specific binding to the receptor in electroplax membranes. 2. To isolate, purify, and chemically characterize novel as well as previously known soft coral and tobacco-derived cembranoids for activity testing. 3. To test the above compounds on activity of the alpha3beta4 and alpha4beta2 receptor subtypes expressed in SH-SY5Y and SH-EPl-h-alpha-4-beta-2 cell lines, respectively. The expected outcome is a better understanding of cembranoid interaction with nAChRs and eventual finding of specific antagonists for neuronal receptor subtypes. This knowledge might eventually result in therapeutic applications related to nicotine addiction stroke or various neurodegenerative diseases.

烟叶含有激动剂尼古丁和各种烟碱乙酰胆碱受体拮抗剂。最后一组由称为西松烷类的环状二萜组成。初步证据表明，这些化合物可能在大脑中积累到足以显著改变尼古丁作用的浓度。西松烷类烟碱拮抗剂 也存在于海洋无脊椎动物，即柳珊瑚中。这些生物体显示出令人惊叹的各种cembrane衍生物，为结构-活性关系研究提供了理想的机会。该提案的目标是：1。确定西松烷类化合物分子的分子特征，这些分子特征影响西松烷类化合物对电器官nAChR的亲和力。为此，最丰富的活性海洋西松烷类化合物，pseudoplexauric酸甲酯（PAME）的合成类似物，将通过有机合成制备和测试的特异性结合受体在electroplax膜。2.分离、纯化和化学表征新的以及先前已知的软珊瑚和烟草衍生的西松烷类化合物，用于活性测试。3.测试上述化合物对分别在SH-SY 5 Y和SH-EP 1-h-α-4-β-2细胞系中表达的α 3 β 4和α 4 β 2受体亚型的活性。预期的结果是更好地了解西松烷类化合物与nAChRs的相互作用，并最终发现神经元受体亚型的特异性拮抗剂。这些知识可能最终导致与尼古丁成瘾、中风或各种神经退行性疾病相关的治疗应用。