Anales RANF

S11-04 STRUCTURAL INSIGHTS INTO MODIFICATIONS TO THE ATP MOLECULE TUNING ITS AGONIST-TO-ANTAGONIST ACTIVITY AT THE P2X RECEPTORS D. Dal Ben, M. Buccioni, C. Lambertucci, G. Marucci, R. Volpini University of Camerino, Camerino (MC), Italy P2XRs are potential therapeutic targets for a wide set of diseases related to inflammation, pain and cancer, including neurological and endocrinological diseases. Hence, the depictions of the mechanism of action of P2XR modulators and structure- activity relationships represent key steps for the rational design of novel molecules able to modulate the receptor function and to be developed as therapeutic agents. Due to its chemical instability in the biological environment and to its lack of selectivity for specific subtypes, the P2XR endogenous ligand ATP was modified by changing the triphosphate chain and the ribose moiety or by inserting substituents in the purine moiety. These modifications led to the development of molecules endowed in some cases with subtype selectivity and increased potency respect to ATP. The modifications on the triphosphate chain were aimed mainly to develop chemically stable compounds without a remarkable change on the compound activity with respect to the corresponding unmodified analogues. Modifications on the sugar moiety by insertion of further groups or by simplification of the ribose ring led in many cases to compounds with a pharmacological profile shifted from full to partial agonist or antagonist. The insertion of substituents on the purine scaffold modulated the potency of the compounds and sometimes their intrinsic activity. With the aid of available crystal structures of P2XRs in complex with the endogenous ligand ATP or analogues (i.e. its derivative TNP-ATP, endowed with an antagonist profile), an interpretation of the mechanism of action of these molecules and the depiction of structure-activity relationships for nucleotide ligands at the P2XRs will be described.