Synthesis and Characterization of High-Affinity 4,4-Difluoro-4-bora-3a,4a-diaza-s-indacene-Labeled Fluorescent Ligands for Human 尾-Adrenoceptors
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- 作者：Jillian G. Baker ; Luke A. Adams ; Karolina Salchow ; Shailesh N. Mistry ; Richard J. Middleton ; Stephen J. Hill ; Barrie Kellam
- 刊名：Journal of Medicinal Chemistry
- 出版年：2011
- 出版时间：October 13, 2011
- 年：2011
- 卷：54
- 期：19
- 页码：6874-6887
- 全文大小：1271K
- 年卷期：v.54,no.19(October 13, 2011)
- ISSN：1520-4804
文摘
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 尾-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 尾-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 鈭?.53 and 鈭?.46 as an antagonist of functional 尾2- and 尾1-mediated responses, respectively). Imaging studies with this compound further confirmed that it can be employed to selectively label the human 尾2-adrenoceptor in single living cells, with receptor-associated binding prevented by preincubation with the nonfluorescent 尾2-selective antagonist 3-(isopropylamino)-1-[(7-methyl-4-indanyl)oxy]butan-2-ol (ICI 118551) (J. Cardiovasc. Pharmacol.1983, 5, 430鈥?37.)