SYNTHESIS AND BIOLOGICAL EVALUATION OF NOVEL A1 ADENOSINE RECEPTOR AGONISTS

A1 adenosine receptor (A1AR) is the best characterized subtype of the four known adenosine receptors.1 Selective A1AR agonists show neuro- and cardio-protective effects, reduce intraocular pressure in glaucoma, and have anticonvulsivant activity. The majority of A1AR agonists are adenosine derivatives and even though many efforts have been carried out, only few drugs in advanced clinical studies are A1AR agonists. The main problem is represented by the significant cardiovascular side effects (bradicardia and hypotension).1 In our previous studies we found that the replacement of the 5’-hydroxy-group by a chlorine atom in N6-substituted adenosine derivatives, improved both the A1AR affinity and selectivity. 5’-Chloro-5’-deoxy-N6-(±)-endo- norbornyl-adenosine (5’Cl5’d-(±)-ENBA) resulted a potent and highly selective A1AR2 agonist showing analgesic effects in a mice model of neuropathic pain.3 Interestingly, at analgesic doses it did not lower blood pressure and locomotor activity in mice.3 Moreover, it reduced dyskinesia evoked by L-DOPA in a mice model of Parkinson disease.4 Based on these interesting findings, a novel series of 5’-modified N6-substitued adenosine derivatives was synthesized and tested in human A1, A2A, A2B, and A3 adenosine receptors binding assay. The most potent and  selective compounds of the series were also assayed in a formalin test in mice. The results of this work will be discussed. 1Fredholm, B.B.; IJzerman, A.P.; Jacobson, K.A.; Linden, J.; Muller, C.E. Pharmacol. Rev. 2011, 63, 1-34. 2Franchetti, 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. 3(a) 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. (b) 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. 4Mango, D.; Bonito-Oliva, A.; Ledonne, A.; Cappellacci, L.; Petrelli, R.; Nisticò, R.; Berretta, N.; Fisone, G.; Mercuri, N.B. Exp. Neurol. 2014, 261, 733−743