Purine nucleotides as potential ligands of G protein-coupled receptor 17 (GPR17)v: molecular modelling and synthesis

The GPR17 receptor, phylogenetically related to both purinergic P2Y and CysLT receptors, is involved in various brain disorders and demyelinating diseases such as multiple sclerosis, stroke, schizophrenia, and depression. GPR17 is a promising therapeutic target; thus, molecules which can bind specifically to this receptor are actively being sought [1]. The evidence that GPR17 is responsive to nucleotides [1] prompted us to synthesize few molecules addressed by docking studies on a GPR17 homology model based on the P2Y1 receptor experimental structure. Chemical synthesis of 8-methylaminoinosinic acid (1) and N2 -alkyl/acyl derivatives of guanylic acid (2-4) (Figure 1) was performed either by phosphorylation of 8-methylaminoinosine, or by N2-alkylation/acylation of guanosine, followed by phosphorylation. In the case of 2, position N2 of the purine ring was activated as a bromo derivative and subjected to displacement with octylamine. N2-Acylations were performed by N2 functionalization with the proper acyl chloride or anhydride through a transient protection strategy. Compounds 2, 3 and 4 were obtained as 2’,3’-O-isopropylidene adducts of the corresponding nucleotides. [1] G. Marucci, D. Dal Ben, C. Lambertucci, A. Martí Navia, A. Spinaci, R. Volpini, and M. Buccioni, Expert Opin. Ther. Pat. 29 (2019) 85-95.