SYNTHESIS AND PHARMACOLOGICAL CHARACTERIZATION OF RIBOSE-MODIFIED ADENOSINE DERIVATIVES AS P1 RECEPTOR LIGANDS

Adenosine, the natural ligand of P1 receptors, is implicated in the control of many physiological and pathological conditions such as inflammation, pain, cardiovascular and central nervous system (CNS) diseases.1 P1 receptors belong to the large family of GPCR receptors and are divided in four subtypes: A1, A2A, A2B and A3 adenosine receptors (ARs). Even though a large number of P1 ligands have been synthesized and characterized byin vitro and in vivo pharmacological studies, only very few of them are commercially available. Modifications at the ribose moiety and substitution at the N6-position of adenosine, lead to adenosine derivatives endowed with increased potency at A1 or A3AR. Our previous SAR studies showed that the replacement of OH at 5’-position of the ribose moiety of N6-substituted adenosine derivatives by a chlorine improved A1AR potency and selectivity versus A3AR, with 5′-chloro-5′-deoxy-N6-(±)-(endo- norborn-2-yl)-adenosine (5′Cl5′d-(±)-ENBA) as one of the most potent and selective A1AR agonists,2 while a 5’-C-ethyl-tetrazolyl moiety maintained the A1AR potency, but restored high A3AR affinity, leading to very potent dual A1AR and A3AR ligands.3 Interestingly, both modifications at 5’-position of adenosine derivatives brought to human A3AR antagonism. In order to further explore the structural determinants of this class of P1 ligands, a new series of ribose- modified N6-substituted adenosine derivatives was synthesized and their pharmacological profile was assayed. The results of this study will be discussed.References 1. Jacobson KA, Muller CE, Neuropharmacology 2015, doi: 10.1016/J.neuropharm.2015.12.001. 2. (a) Franchetti, P.; Cappellacci, L.; Vita, P.; Petrelli, R.; Lavecchia, A.; Kachler, S.; Klotz, K.-N.; Marabese, I.; Luongo, L.; Maione, S.; Grifantini, M. J. Med. Chem. 2009, 52, 2393−2406. (b) Luongo, L.; Petrelli, R.; Gatta, L.; Giordano, C.; Guida, F.; Vita, P.; Franchetti, P.; Grifantini, M.; De Novellis, V.; Cappellacci, L.; Maione, S. Molecules 2012, 17, 13712−13726. (c) Luongo, L.; Guida, F.; Imperatore, R.; Napolitano, F.; Gatta, L.; Cristino, L.; Giordano, C.; Siniscalco, D.; Di Marzo, V.; Bellini, G.; Petrelli, R.; Cappellacci, L.; Usiello, A.; de Novellis, V.; Rossi, F.; Maione, S. Glia 2014, 62, 122−132. 3. Petrelli, R.; Torquati, I.; Kachler, S.; Luongo, L.; Maione, S.; Franchetti, P.; Grifantini, M.; Novellino, E.; Lavecchia, A.; Klotz, K.-N-; Cappellacci, L. J. Med. Chem. 2015, 58, 2560-2566.