Synthesis and Characterization of High-Affinity 4,4-Difluoro-4-bora-3a,4a-diaza-<i>s</i>-indacene-Labeled Fluorescent Ligands for Human β-Adrenoceptors


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 (<b>18a</b>) had the highest affinity (log <i>K</i><sub>D</sub> 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) (<i>J. Cardiovasc. Pharmacol.</i> <b>1983</b>, <i>5</i>, 430–437.

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Last time updated on 12/02/2018

This paper was published in FigShare.

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