New 7-amino-2-phenylpyrazolo[4,3-d]pyrimidine derivatives, substituted at the 5-position with aryl(alkyl)amino- and 4-substituted-piperazin-1-yl- moieties, were synthesized with the aim of targeting human (h) adenosine A1 and/or A2A receptor subtypes. On the whole, the novel derivatives 1–24 shared scarce or no affinities for the off-target hA2B and hA3 ARs. The 5-(4-hydroxyphenethylamino)- derivative 12 showed both good affinity (Ki ¼150 nM) and the best selectivity for the hA2A AR while the 5-benzylamino-substituted 5 displayed the best combined hA2A (Ki ¼123 nM) and A1 AR affinity (Ki ¼25 nM). The 5-phenethylamino moiety (compound 6) achieved nanomolar affinity (Ki ¼11 nM) and good selectivity for the hA1 AR. The 5-(N4-substituted-piperazin-1-yl) derivatives 15–24 bind the hA1 AR subtype with affinities falling in the high nanomolar range. A structure-based molecular modeling study was conducted to rationalize the experimental binding data from a molecular point of view using both molecular docking studies and Interaction Energy Fingerprints (IEFs) analysis.

The role of 5-arylalkylamino- and 5-piperazino- moieties on the 7-aminopyrazolo[4,3-d]pyrimidine core in affecting adenosine A1 and A2A receptor affinity and selectivity profiles / Squarcialupi, Lucia; Betti, Marco; Catarzi, Daniela; Varano, Flavia; Falsini, Matteo; Ravani, Annalisa; Pasquini, Silvia; Vincenzi, Fabrizio; Salmaso, Veronica; Sturlese, Mattia; Varani, Katia; Moro, Stefano; Colotta, Vittoria. - In: JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY. - ISSN 1475-6366. - STAMPA. - 32:(2017), pp. 248-263. [10.1080/14756366.2016.1247060]

The role of 5-arylalkylamino- and 5-piperazino- moieties on the 7-aminopyrazolo[4,3-d]pyrimidine core in affecting adenosine A1 and A2A receptor affinity and selectivity profiles

SQUARCIALUPI, LUCIA;BETTI, MARCO;CATARZI, DANIELA;VARANO, FLAVIA;FALSINI, MATTEO;COLOTTA, VITTORIA
2017

Abstract

New 7-amino-2-phenylpyrazolo[4,3-d]pyrimidine derivatives, substituted at the 5-position with aryl(alkyl)amino- and 4-substituted-piperazin-1-yl- moieties, were synthesized with the aim of targeting human (h) adenosine A1 and/or A2A receptor subtypes. On the whole, the novel derivatives 1–24 shared scarce or no affinities for the off-target hA2B and hA3 ARs. The 5-(4-hydroxyphenethylamino)- derivative 12 showed both good affinity (Ki ¼150 nM) and the best selectivity for the hA2A AR while the 5-benzylamino-substituted 5 displayed the best combined hA2A (Ki ¼123 nM) and A1 AR affinity (Ki ¼25 nM). The 5-phenethylamino moiety (compound 6) achieved nanomolar affinity (Ki ¼11 nM) and good selectivity for the hA1 AR. The 5-(N4-substituted-piperazin-1-yl) derivatives 15–24 bind the hA1 AR subtype with affinities falling in the high nanomolar range. A structure-based molecular modeling study was conducted to rationalize the experimental binding data from a molecular point of view using both molecular docking studies and Interaction Energy Fingerprints (IEFs) analysis.
2017
32
248
263
Squarcialupi, Lucia; Betti, Marco; Catarzi, Daniela; Varano, Flavia; Falsini, Matteo; Ravani, Annalisa; Pasquini, Silvia; Vincenzi, Fabrizio; Salmaso,...espandi
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1080810
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