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Fluorescent ligands represent powerful tools for biological studies and are considered attractive alternatives to radioligands. In this study, we developed fluorescent antagonists for A2B adenosine receptors (A2BARs), which are targeted by antiasthmatic xanthines and were proposed as novel targets in immuno-oncology. Our approach was to merge a small borondipyrromethene (BODIPY) derivative with the pharmacophore of 8-substituted xanthine derivatives. On the basis of the design, synthesis, and evaluation of model compounds, several fluorescent ligands were synthesized. Compound 29 (PSB-12105), which displayed high affinity for human, rat, and mouse A2BARs (Ki = 0.2-2 nM) and high selectivity for this AR subtype, was selected for further studies. A homology model of the human A2BAR was generated, and docking studies were performed. Moreover, 29 allowed us to establish a homogeneous receptor-ligand binding assay using flow cytometry. These compounds constitute the first potent, selective fluorescent A2BAR ligands and are anticipated to be useful for a variety of applications. [ABSTRACT FROM AUTHOR]

Abstract: A series of 2-hydrazinyladenosine derivatives was synthesized and investigated in radioligand binding studies for their affinity at the adenosine receptor subtypes with the goal to obtain potent and A2AAR selective agonists and to explore the structure–activity relationships of this class of compounds at A2AAR. Modifications included introduction of a second sugar moiety at position 2 of adenosine to form new bis-sugar nucleosides and/or modifications of the 2-position linker in different ways. The performed modifications were found to produce compounds with relatively high A2AAR affinity and very high selectivity toward A2AAR. The most potent bis-sugar nucleoside was obtained with the d-galactose derivative 16 which exhibited a K i value of 329nM at A2AAR with marked selectivity against the other AR subtypes. In another set of compounds, compound 3 was modified via replacement of its cyclic structure with mono- and disubstituted phenyl moieties and the resulting hydrazones 10–14 were found to have low nanomolar affinity for A2AAR. In addition to 3, compounds 10, 11 and 13 have been identified as the most potent compounds in the present series with K i values of 16.1, 24.4, and 12.0nM, respectively, at rat A2AAR. Species differences were tested and found to exist in different rates. Functional properties of the most potent compounds 10, 11, 13 and 16 were assessed showing that the compounds acted as agonists at A2AAR. [Copyright &y& Elsevier]

Fluorescent ligands represent powerful tools for biological studies and are considered attractive alternatives to radioligands. In this study, we developed fluorescent antagonists for A 2B adenosine receptors (A 2B ARs), which are targeted by antiasthmatic xanthines and were proposed as novel targets in immuno-oncology. Our approach was to merge a small borondipyrromethene (BODIPY) derivative with the pharmacophore of 8-substituted xanthine derivatives. On the basis of the design, synthesis, and evaluation of model compounds, several fluorescent ligands were synthesized. Compound 29 (PSB-12105), which displayed high affinity for human, rat, and mouse A 2B ARs ( K i = 0.2-2 nM) and high selectivity for this AR subtype, was selected for further studies. A homology model of the human A 2B AR was generated, and docking studies were performed. Moreover, 29 allowed us to establish a homogeneous receptor-ligand binding assay using flow cytometry. These compounds constitute the first potent, selective fluorescent A 2B AR ligands and are anticipated to be useful for a variety of applications.

Adenosine A2A receptor agonists for the local treatment of inflammatory bowel disease (IBS) were designed and synthesized. Polar groups were introduced to prevent peroral absorption and subsequent systemic, e.g., hypotensive, side effects. 4-(2-{6-Amino-9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-9H-purin-2-ylthio}ethyl)benzenesulfonic acid (7, PSB-0777) was selected for further evaluation in rat ileum/jejunum preparations in ex vivo experiments. Compound 7 significantly improved impaired acetylcholine-induced contractions induced by 2,4,6-trinitrobenzenesulfonic acid and showed synergism with an A2B-selective antagonist. Thus, nonabsorbable, locally active A2A agonists, as a monotherapy or in combination with an A2B antagonist, may be an efficient novel treatment for IBS, preventing the severe systemic side effects of known A2A agonists.