Synthesis and evaluation of adenosine derivatives as A1, A2A, A2B and A3 adenosine receptor ligands containing boron clusters as phenyl isosteres and selective A3 agonists

Abstract

A series of adenosine and 2'-deoxyadenosine pairs modified with a 1,12-dicarba-closo-dodecaborane cluster or alternatively with a phenyl group at the same position was synthesized, and their affinity was determined at A₁, A_2A, A_2B and A₃ adenosine receptors (ARs). While AR affinity differences were noted, a general tendency to preferentially bind A₃ AR over other ARs was observed for most tested ligands. In particular, 5'-ethylcarbamoyl-N⁶-(3-phenylpropyl)adenosine (18), N⁶-(3-phenylpropyl)-2-chloroadenosine (24) and N⁶-(3-phenylpropyl)adenosine (40) showed nanomolar A₃ affinity (K_i 4.5, 6.4 and 7.5 nM, respectively). Among the boron cluster-containing compounds, the highest A₃ affinity (K_i 206 nM) was for adenosine derivative 41 modified at C2. In the matched molecular pairs, analogs bearing boron clusters were found to show lower binding affinity for adenosine receptors than the corresponding phenyl analogs. Nevertheless, interestingly, several boron cluster modified adenosine ligands showed significantly higher A₃ receptor selectivity than the corresponding phenyl analogs: 7vs. 8, 15vs. 16, 17vs. 18.

Keywords: Adenosine; Agonists; Antagonists; Boron cluster; Nucleosides; Purinergic receptors; Selectivity.