GPR17 ligands: synthesis and characterization of new potent agonists

The G protein-coupled receptor GPR17, a dualistic receptor that responds to nucleotides and cysteinyl leukotrienes, is believed to represent a novel target for the development of new relevant therapeutic approaches to human stroke and ischemic damage. [35S]GTPγS binding assay, performed on transfected 1321N1 cells, demonstrated that 2-phenylethynylATP behaves as a strong agonist (EC50=36 pM) of the receptor [1]. On the other hand, N6-methylATP showed antagonist activity as well as some purine nucleotide bisphosphates. On these bases, in the search for potent GPR17 ligands, 2-phenylethynyl ATP derivatives bearing alkyl groups in the N6 position, a new bisphosphate derivative, and a stable analogue bearing the aforementioned 2-phenylethynyl chain were synthesized. Biological studies showed that the new compounds behave as strong agonists of GPR17 with EC50 ranging from low nanomolar to subnanomolar values; hence, they could be efficacious tools for the further characterization of the receptor and to study its role in neurodegeneration processes.