Synthesis and characterization of high-affinity 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene-labeled fluorescent ligands for human β-adrenoceptors.
Synthesis and characterization of high-affinity 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene-labeled fluorescent ligands for human β-adrenoceptors.
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DOI：
10.1021/jm2008562
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发表时间：
2011-10-13
影响因子：
7.3
通讯作者：
Kellam, Barrie
中科院分区：
文献类型：
--
作者：
Baker, Jillian G.;Adams, Luke A.;Salchow, Karolina;Mistry, Shailesh N.;Middleton, Richard J.;Hill, Stephen J.;Kellam, Barrie
利用非侵入性荧光技术在单细胞和单分子水平上研究G蛋白偶联受体药理学的实践越来越多，这需要高质量的荧光配体。为此，本研究评估了一系列新的人β-肾上腺素受体家族的红色发光配体。在正构配体普萘洛尔、阿普洛尔和吲哚洛尔的基础上，将合成的接头修饰的同系物偶联到市售荧光团BODIPY 630/650-X上。这为普萘洛尔和烯丙洛尔衍生物产生了高亲和力的β-肾上腺素受体荧光配体;然而，基于吲哚洛尔的产品显示出较低的亲和力。荧光二甘醇连接的普萘洛尔衍生物（18 a）具有最高的亲和力（作为功能性β2和β1介导反应的拮抗剂，log KD分别为-9.53和-8.46）。该化合物的成像研究进一步证实，它可用于选择性标记单个活细胞中的人β2-肾上腺素受体，通过与非荧光β2-选择性拮抗剂3-（异丙基氨基）-1-[（7-甲基-4-茚满基）氧基]丁-2-醇（ICI 118551）预孵育，可阻止受体相关结合
The growing practice of exploiting noninvasive fluorescence-based techniques to study G protein-coupled receptor pharmacology at the single cell and single molecule level demands the availability of high-quality fluorescent ligands. To this end, this study evaluated a new series of red-emitting ligands for the human β-adrenoceptor family. Upon the basis of the orthosteric ligands propranolol, alprenolol, and pindolol, the synthesized linker-modified congeners were coupled to the commercially available fluorophore BODIPY 630/650-X. This yielded high-affinity β-adrenoceptor fluorescent ligands for both the propranolol and alprenolol derivatives; however, the pindolol-based products displayed lower affinity. A fluorescent diethylene glycol linked propranolol derivative (18a) had the highest affinity (log KD of −9.53 and −8.46 as an antagonist of functional β2- and β1-mediated responses, respectively). Imaging studies with this compound further confirmed that it can be employed to selectively label the human β2-adrenoceptor in single living cells, with receptor-associated binding prevented by preincubation with the nonfluorescent β2-selective antagonist 3-(isopropylamino)-1-[(7-methyl-4-indanyl)oxy]butan-2-ol (ICI 118551)
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影响因子：
7.3
作者：
Hill, SJ
通讯作者：
Hill, SJ
DOI：
10.1124/jpet.104.082875
发表时间：
2005-06-01
影响因子：
3.5
作者：
Baker, JG
通讯作者：
Baker, JG
影响因子：
2.9
作者：
HEITHIER, H;HALLMANN, D;HELMREICH, EJM
通讯作者：
HELMREICH, EJM
影响因子：
3.6
作者：
Baker, JG;Hall, IP;Hill, SJ
通讯作者：
Hill, SJ
影响因子：
3.6
作者：
Baker, JG;Hall, IP;Hill, SJ
通讯作者：
Hill, SJ