Adenine nucleotides as potent and selective GPR17 modulators

The G protein-coupled receptor GPR17 is expressed by neuronal cells in various brain areas, where it modulates oligodendrocytes maturation and differentiation and myelination process. The altered expression and activity of this receptor are associated with neurodegenerative processes like myelinating disorders, brain ischemia, and multiple sclerosis. Hence, the development of pharmacological tools able to modulate GPR17 activity may represent a potential key strategy to treat CNS disorders. In this work, we developed adenine nucleotides consisting in 5′-triphosphate derivatives, their α,β- or β,γ-modified triphosphate analogues, and 3′,5′-bisphosphate derivatives, with the adenine core presenting further modifications given by the presence of substituents at the 2- and/or N 6 -position. Results of biological evaluation at HEK293 L9–2 cells transiently transfected with human GPR17 demonstrated that the novel compounds are endowed with nanomolar or picomolar potency and various profiles of efficacy. GPR17 selectivity of these molecules was also demonstrated by evaluating them at HEK293 L9–2 cells transiently transfected with human purinergic P2Y 12 , P2Y 13 , and P2Y 14 receptors. • GPR17 is a potential target to treat neurodegenerative diseases. • Substituted adenine nucleotides were developed as GPR17 agonists and antagonists. • The novel compounds showed nanomolar/picomolar potency as GPR17 modulators. • Selectivity versus purinergic human P2Y 12 , P2Y 13 , and P2Y 14 was assessed.