Synthesis and molecular modeling of purine ribonucleotides as potential ligands of the human G protein-coupled receptor 17 (GPR17)

GPCRs (G Protein-Coupled Receptors) are important drug targets in medicinal chemistry [1]. The GPR17 receptor, phylogenetically related to both purinergic P2Y and CysLT receptors, is usually over-expressed in the damaged brain tissue and is involved in various disorders characterized by demyelination, such as multiple sclerosis and stroke. Experimental data have shown that it is responsive to both agonists (e.g. nucleotides and their adducts) and antagonists (e.g. Cangrelor and Montelukast) [2]. Therefore, the human GPR17 receptor is a promising therapeutic target for treatment of neurodegenerative diseases [3]. This evidence prompted us to perform docking studies aided by molecular modeling on a homology model (based on P2Y1 receptors). Among the selected molecules, 8-methylaminoinosinic acid (1) and three N2-alkyl/acyl derivatives of guanylic acid (2-4) emerged as the best potential ligands. As a result, their synthesis was carried out. Compound 1 was obtained by direct phosphorylation of 8-methylaminoinosine, previously prepared by amination of 8-bromoinosine. In the case of 2, position N2 of the purine ring was activated as a bromo derivative and subjected to displacement with n-octylamine. As for 3 and 4, N2-acylations were performed by treatment with a 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. Binding assays will be carried out by Surface Plasmon Resonance (SPR) [4], which has been demonstrated as a reliable technique for the systematic identification of agonists and antagonists of GPCRs, including GPR17 as recently demonstrated by our group [5]. [1] D. Wacker, R. C. Stevens, B. L. Roth, Cell 2017, 170, 414-427. [2] P. Ciana, M. Fumagalli, M.L. Trincavelli, C. Verderio, P. Rosa, D. Lecca, S. Ferrario, C. Parravicini, V. Capra, P. Gelosa, U. Guerrini, S. Belcredito, M. Cimino, L. Sironi, E. Tremoli, G.E. Rovati, C. Martini and M.P. Abbracchio, EMBO J 2006, 25, 4615-4627. [3] G. Marucci, D. Dal Ben, C. Lambertucci, A. Marti Navia, A. Spinaci, R. Volpini and M. Buccioni, Expert Opin. Ther. Pat. 2019, 29, 85-95. [4] D.-S. Wang, S.-K. Fan, Sensors 2016, 16, 1175-1192. [5] D. Capelli, C. Parravicini, G. Pochetti, R. Montanari, C. Temporini, M. Rabuffetti, M. L. Trincavelli, S. Daniele, M. Fumagalli, S. Saporiti, E. Bonfanti, M. P. Abbracchio, I. Eberini, S. Ceruti, E. Calleri, S. Capaldi, Front. Chem. 2020, 7, 910