Anales RANF

P.83 NEW 4’-TETRAZOLYL ADENOSINE DERIVATIVES AS POTENTIAL AGENTS FOR WOUND HEALING A. Spinaci 1 , M. Buccioni 1 , D. Dal Ben 1 , C. Lambertucci 1 , G. Marucci 1 , M.A. Navia 1 , M. A. Ngouadijeu 1 , R. Volpini 1 . 1 University of Camerino, School of Pharmacy, Medicinal Chemistry Unit, 62032 Camerino, Italy Ligands for A 2A adenosine receptors (ARs) are potential therapeutic candidates for many disorders and seem to regulate the wound healing process. The introduction of substituents with different length in the 2-position of adenosine (Ado) and 5’- N - ethylcarboxamidoAdo (NECA) favours the interaction of the resulted nucleosides with the A 2A AR. Known examples of such compounds are 2-phenylethylthioNECA (VT 7) and CGS21680 that possess high A 2A AR affinity but moderate selectivity. Furthermore, it has been reported that a tetrazolyl moiety in 4’-position of 2-alkylaminoAdo derivatives led to compounds endowed with a dual effect, resulting A 2A AR agonists and A 3 AR antagonists. Starting from these observations, a new series 4’-tetrazolyl Ado derivatives bearing different arylalkyl-thio, -amino, and -oxy chains in 2-position were designed and synthesized. All the new compounds were tested in binding and functional assays at human ARs and their ability to facilitate wound healing has been evaluated by determining their efficacy to improve human fibroblast migration. Binding data showed that the substitution of the 5’-N-ethylcarboxamido group of VT 7 with the 4’- ethyltetrazolyl substituent favours the interaction with the A 2A AR (2-phenylethylthio- 4’-ethyltetrazolylAdo, K i = 5.8 nM versus VT 7, K i = 24 nM). The functional study confirms the dual behaviour at ARs of the new derivatives (2-phenylethylthio-4’- ethyltetrazolylAdo, hA 2A AR EC 50 = 160 nM and hA 3 AR IC 50 = 80 nM). Moreover, from the in vitro evaluation of fibroblast migration emerged that most of the new compounds were able to improve cell migration better than epidermal growth factor (EGF), which was used as the positive control. Hence, the new 4’-ethyltetrazolyl-2-substituted Ado derivatives could be as new tools useful in wound healing.