当前位置: X-MOL 学术Insect Biochem. Mol. Biol. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Discovery of antagonists of tick dopamine receptors via chemical library screening and comparative pharmacological analyses.
Insect Biochemistry and Molecular Biology ( IF 3.8 ) Pub Date : 2012-12-06 , DOI: 10.1016/j.ibmb.2012.07.011
Karin F K Ejendal 1 , Jason M Meyer , Tarsis F Brust , Larisa V Avramova , Catherine A Hill , Val J Watts
Affiliation  

Ticks transmit a wide variety of disease causing pathogens to humans and animals. Considering the global health impact of tick-borne diseases, there is a pressing need to develop new methods for vector control. We are exploring arthropod dopamine receptors as novel targets for insecticide/acaricide development because of their integral roles in neurobiology. Herein, we developed a screening assay for dopamine receptor antagonists to further characterize the pharmacological properties of the two D₁-like dopamine receptors (Isdop1 and Isdop2) identified in the Lyme disease vector, Ixodes scapularis, and develop a screening assay for receptor antagonists. A cell-based, cyclic AMP luciferase reporter assay platform was implemented to screen the LOPAC(1280) small molecule library for Isdop2 receptor antagonists, representing the first reported chemical library screen for any tick G protein-coupled receptor. Screening resulted in the identification of 85 "hit" compounds with antagonist activity at the Isdop2 receptor. Eight of these chemistries were selected for confirmation assays using a direct measurement of cAMP, and the effects on both Isdop1 and Isdop2 were studied for comparison. Each of these eight compounds showed antagonistic activity at both Isdop1 and Isdop2, although differences were observed regarding their relative potencies. Furthermore, comparison of the pharmacological properties of the tick dopamine receptors with that of the AaDOP2 receptor from the yellow fever mosquito and the human dopamine D₁ receptor (hD₁) revealed species-specific pharmacological profiles of these receptors. Compounds influencing dopaminergic functioning, such as the dopamine receptor antagonists discovered here, may provide lead chemistries for discovery of novel acaricides useful for vector control

中文翻译:

通过化学文库筛选和比较药理分析发现壁虱多巴胺受体拮抗剂。

壁虱将各种引起病原体的疾病传播给人类和动物。考虑到tick传播疾病对全球健康的影响,迫切需要开发新的媒介控制方法。我们正在研究节肢动物多巴胺受体作为杀虫剂/杀螨剂开发的新型靶标,因为它们在神经生物学中起着不可或缺的作用。本文中,我们开发了一种针对多巴胺受体拮抗剂的筛选方法,以进一步表征在莱姆病载体肩vector突肌中鉴定的两个D₁样多巴胺受体(Isdop1和Isdop2)的药理特性,并开发一种针对受体拮抗剂的筛选方法。实施了基于细胞的环状AMP荧光素酶报告基因检测平台,以筛选LOPAC(1280)小分子文库中的Isdop2受体拮抗剂,代表首次报道的任何壁虱G蛋白偶联受体的化学文库筛选。筛选导致鉴定出对Isdop2受体具有拮抗活性的85种“命中”化合物。使用直接测量cAMP的方法选择了8种化学试剂进行确认分析,并研究了对Isdop1和Isdop2的影响以进行比较。这八种化合物中的每一种都对Isdop1和Isdop2均表现出拮抗活性,尽管在它们的相对效力方面存在差异。此外,壁虱多巴胺受体的药理特性与黄热蚊和人多巴胺D 1受体(hD 3)的AaDOP2受体的药理特性的比较揭示了这些受体的物种特异性药理学特征。
更新日期:2012-08-07
down
wechat
bug