Synthesis and characterization of high-affinity 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene-labeled fluorescent ligands for human beta-adrenoceptors.
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Baker JG, Adams LA, Salchow K, Mistry SN, Middleton RJ, Hill SJ, Kellam B
Synthesis and characterization of high-affinity 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene-labeled fluorescent ligands for human beta-adrenoceptors.
J Med Chem. 2011 Oct 13;54(19):6874-87. doi: 10.1021/jm2008562. Epub 2011 Sep 16.
- PubMed ID
- 21870877 [ View in PubMed]
- Abstract
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 beta-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 beta-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 K(D) of -9.53 and -8.46 as an antagonist of functional beta2- and beta1-mediated responses, respectively). Imaging studies with this compound further confirmed that it can be employed to selectively label the human beta2-adrenoceptor in single living cells, with receptor-associated binding prevented by preincubation with the nonfluorescent beta2-selective antagonist 3-(isopropylamino)-1-[(7-methyl-4-indanyl)oxy]butan-2-ol (ICI 118551) ( J. Cardiovasc. Pharmacol.1983, 5, 430-437. ).
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Alprenolol Beta-1 adrenergic receptor Kd (nM) 178 N/A N/A Details Alprenolol Beta-1 adrenergic receptor Kd (nM) 4.3 N/A N/A Details Alprenolol Beta-1 adrenergic receptor Kd (nM) 11 N/A N/A Details Alprenolol Beta-3 adrenergic receptor Kd (nM) 76 N/A N/A Details Alprenolol Beta-3 adrenergic receptor Kd (nM) 138 N/A N/A Details Pindolol Beta-1 adrenergic receptor Kd (nM) 2.4 N/A N/A Details Pindolol Beta-1 adrenergic receptor Kd (nM) 2.6 N/A N/A Details Pindolol Beta-3 adrenergic receptor Kd (nM) 166 N/A N/A Details Propranolol Beta-1 adrenergic receptor Kd (nM) 200 N/A N/A Details Propranolol Beta-1 adrenergic receptor Kd (nM) 1.8 N/A N/A Details Propranolol Beta-1 adrenergic receptor Kd (nM) 6 N/A N/A Details Propranolol Beta-3 adrenergic receptor Kd (nM) 162 N/A N/A Details Propranolol Beta-3 adrenergic receptor Kd (nM) 214 N/A N/A Details