- Exploring the 2- and 5-positions of the pyrazolo[4,3-d]pyrimidin-7-amino scaffold to target human A1 and A2A adenosine receptors
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A new series of 7-aminopyrazolo[4,3-d]pyrimidine derivatives (1-31) were synthesized to evaluate some structural modifications at the 2- and 5-positions aimed at shifting affinity towards the human (h) A2A adenosine receptor (AR) or both hA2A and hA1 ARs. The most active compounds were those featured by a 2-furyl or 5-methylfuran-2-yl moiety at position 5, combined with a benzyl or a substituted-benzyl group at position 2. Several of these derivatives (22-31) displayed nanomolar affinity for the hA2A AR (Ki = 3.62-57 nM) and slightly lower for the hA1 ARs, thus showing different degrees (3-22 fold) of hA2A versus hA1 selectivity. In particular, the 2-(2-methoxybenzyl)-5-(5-methylfuran-2-yl) derivative 25 possessed the highest hA2A and hA1 AR affinities (Ki = 3.62 nM and 18 nM, respectively) and behaved as potent antagonist at both these receptors (cAMP assays). Its 2-(2-hydroxybenzyl) analog 26 also showed a high affinity for the hA2A AR (Ki = 5.26 nM) and was 22-fold selective versus the hA1 subtype. Molecular docking investigations performed at the hA2A AR crystal structure and at a homology model of the hA1 AR allowed us to represent the hypothetical binding mode of our derivatives and to rationalize the observed SARs.
- Squarcialupi, Lucia,Falsini, Matteo,Catarzi, Daniela,Varano, Flavia,Betti, Marco,Varani, Katia,Vincenzi, Fabrizio,Dal Ben, Diego,Lambertucci, Catia,Volpini, Rosaria,Colotta, Vittoria
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p. 2794 - 2808
(2016/06/08)
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- 2-Arylpyrazolo[4,3-d]pyrimidin-7-amino derivatives as new potent and selective human A3 adenosine receptor antagonists. Molecular modeling studies and pharmacological evaluation
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On the basis of our previously reported 2-arylpyrazolo[4,3-d]pyrimidin-7- ones, a set of 2-arylpyrazolo[4,3-d]pyrimidin-7-amines were designed as new human (h) A3 adenosine receptor (AR) antagonists. Lipophilic groups with different steric bulk were introduced at the 5-position of the bicyclic scaffold (R5 = Me, Ph, CH2Ph), and different acyl and carbamoyl moieties (R7) were appended on the 7-amino group, as well as a para-methoxy group inserted on the 2-phenyl ring. The presence of acyl groups turned out to be of paramount importance for an efficient and selective binding at the hA3 AR. In fact, most of the 7-acylamino derivatives showed low nanomolar affinity (Ki = 2.5-45 nM) and high selectivity toward this receptor. A few selected pyrazolo[4,3-d]pyrimidin-7-amides were effective in counteracting oxaliplatin-induced apoptosis in rat astrocyte cell cultures, an in vitro model of neurotoxicity. Through an in silico receptor-driven approach the obtained binding data were rationalized and the molecular bases of the observed hA3 AR affinity and hA3 versus hA2A AR selectivity were explained.
- Squarcialupi, Lucia,Colotta, Vittoria,Catarzi, Daniela,Varano, Flavia,Filacchioni, Guido,Varani, Katia,Corciulo, Carmen,Vincenzi, Fabrizio,Borea, Pier Andrea,Ghelardini, Carla,Di Cesare Mannelli, Lorenzo,Ciancetta, Antonella,Moro, Stefano
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p. 2256 - 2269
(2013/05/21)
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- 2-Phenylpyrazolo[4,3-d]pyrimidin-7-one as a new scaffold to obtain potent and selective human a3 adenosine receptor antagonists: new insights into the receptor-antagonist recognition
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A molecular simplification approach of previously reported 2-arylpyrazolo[3,4-c]quinolin-4-ones was applied to design 2-arylpyrazolo[4,3-d] pyrimidin-7-one derivatives as new human A3 adenosine receptor antagonists. Substituents with different
- Lenzi, Ombretta,Colotta, Vittoria,Catarzi, Daniela,Varano, Flavia,Poli, Daniela,Filacchioni, Guido,Varani, Katia,Vincenzi, Fabrizio,Borea, Pier Andrea,Paoletta, Silvia,Morizzo, Erika,Moro, Stefano
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experimental part
p. 7640 - 7652
(2010/08/03)
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