1335302-66-3Relevant academic research and scientific papers
Fragment evolution for GPCRs: The role of secondary binding sites in optimization
Aranyodi, Vivien A.,Baker, Jillian G.,Balzer, Frank,Chevillard, Florent,Kolb, Peter,Kelemen, ádám,Keser?, Gy?rgy M.
, p. 10516 - 10519 (2021/10/19)
We developed a docking-based fragment evolution approach that extends orthosteric fragments towards a less conserved secondary binding pocket of GPCRs. Evaluating 13?000 extensions for the β1- and β2-adrenergic receptors we synthesized and tested 112 bitopic molecules. Our results confirmed the positive contribution of the secondary binding pocket to both potency and selectivity optimizations.
Synthesis and characterization of high-affinity 4,4-difluoro-4-bora-3a,4a- diaza-s-indacene-labeled fluorescent ligands for human β-adrenoceptors
Baker, Jillian G.,Adams, Luke A.,Salchow, Karolina,Mistry, Shailesh N.,Middleton, Richard J.,Hill, Stephen J.,Kellam, Barrie
, p. 6874 - 6887 (2011/12/15)
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) (J. Cardiovasc. Pharmacol.1983, 5, 430-437.)
