Synthesis and structure–activity relationships of 2-hydrazinyladenosine derivatives as A2A adenosine receptor ligands

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 Ki 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 Ki 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.