Structure determination and structure-activity relationship of DOP Arelated compounds

DOP相关化合物的结构测定及构效关系

基本信息

批准号：
18390076
负责人：
GOSHIMA Yoshio
金额：
$ 10.3万
依托单位：
Yokohama City University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

项目摘要

We have proposed that L-3,4-dihydroxyphenylalanine (DOPA), the precursor of dopamine, is a neurotransmitter in the central nervous system. However its specific receptor(s) have not been determined yet. In this proposal, we have tried to identify specific ligands for DOPA recognistion site(s), namely DOPAreceptor(s), and investigate structure-activity relationship by using blood-pressure monitoring system in anaesthetized rats. DOPA or L-threo-DOPS, a precursor of noradrenaline, when microinjected into the nucleus tractus solitarii (NTS), induces depressor and baradycardic responses. By using HPLC, we found an active fraction of DOPA or DOPS-containing solution other than that of DOPA and DOPS itself that induced depressor and bradycardic responses. We obtained A113 and S122 fractions from DOPA and DOPS-containing solutions, respectively, both of which were active in inducing the cardiovascular responses in anaesthetized rats. In addition, these responses were antagonized by L-DOPA cycl … More ohexylester (DOPA CHE), an competitive antagonist for DOPA, thereby suggesting that some unknown active substances in DOPA and DOPS solution induced depressor and bradycardic responses through the recognition site(s) for DOPA. We are now trying further purification, identification and structural determination of these substances.The second project aimed at identification and characterization of a DOPA receptor candidate gene, C06H5.7 in C elegans. Using Xenopus laevis oocyte expression system, we identified a candidate G-protein-coupled receptor, that mediates current response to DOPA C06H5.7 was expressed in ASH chemosensory neurons. In C06H5.7 mutant animals, the avoidance response to undiluted benzaldehyde, but not to 1-octanol, was attenuated. C06H5.7, when exogenously expressed in ASH neurons, rescued the responsiveness to benzaldehyde. Furthermore, we found some water-soluble substance as a novel repellent acting on this receptor in C elegans. These results indicate that C06H5.7 is not a receptor for DOPA but the first chemosensory receptor that mediates aversive response to volatile and water soluble chemorepellents. Less

我们已经提出，多巴胺的前体L-3,4-二羟基苯胺（DOPA）是中枢神经系统中的神经递质。但是，尚未确定其特定的受体。在此提案中，我们试图确定DOPA识别位点的特定配体，即多户受体，并通过使用麻醉大鼠中的血压监测系统来研究结构活性关系。 Dopa或L-Threo-Dops是去甲肾上腺素的前体时，当将微介入核管Solitarii（NTS）中时，会诱导抑郁症和巴拉多反应。通过使用HPLC，我们发现了含DOPA或DOP的活性分数，除了DOPA和DOPS本身的溶液，可诱导抑郁症和心动过缓响应。我们分别从DOPA和含DOP的溶液中获得了A113和S122馏分。此外，这两个响应都被L-DOPA Cycl吞噬了l-dopa Cycl…更多的OHExylester（Dopa Che）（Dopa Che），这是DOPA的竞争性拮抗剂，它是DOPA和DOP诱导的DOPS诱导的一些不知名的活性物质，并建议使用DOPA和BRADCARD，SE）soveric and dopa seption（Dopa Che）。 Dopa。我们现在正在尝试进一步纯化，鉴定和结构性确定这些物质。第二个项目旨在识别和表征DOPA受体C06H5.7在C秀丽隐杆线虫中。使用Xenopus laevis卵母细胞表达系统，我们鉴定了一个候选G蛋白偶联受体，该受体介导了当前对DOPA C06H5.7的反应，在灰化学效率神经元中表达。在C06H5.7突变动物中，降低了对未稀释的苯甲醛的回避反应，但对1-辛醇的反应被减弱。 C06H5.7在灰神经元中清楚地表达时，对苯甲醛的反应做出了反应。此外，我们发现了一些水溶性物质是一种新颖的驱虫剂，该物质作用于秀丽隐杆线虫中的这种受体。这些结果表明，C06H5.7不是DOPA的受体，而是第一个介导对挥发性和水溶性化学物质的厌恶反应的化学感应受体。较少的