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EnglishNew 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 = 150 nM) and the best selectivity for the hA2A AR while the 5-benzylamino-substituted 5 displayed the best combined hA2A (Ki = 123 nM) and A1 AR affinity (Ki = 25 nM). The 5-phenethylamino moiety (compound 6) achieved nanomolar affinity (Ki = 11 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.[Formula: see text].
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| Data di pubblicazione: | 2017 | |
| Titolo: | 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 | |
| Autori: | 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 | |
| Rivista: | JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY | |
| Parole Chiave: | Adenosine A1 and A2A receptor antagonists; G protein-coupled receptors; ligand-receptor modeling studies; pyrazolo[4,3-d]pyrimidines; Adenosine A1 Receptor Antagonists; Adenosine A2 Receptor Antagonists; Dose-Response Relationship, Drug; Humans; Molecular Docking Simulation; Molecular Structure; Pyrimidines; Receptor, Adenosine A1; Receptor, Adenosine A2A; Structure-Activity Relationship; Pharmacology; Drug Discovery3003 Pharmaceutical Science | |
| Abstract in inglese: | 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 = 150 nM) and the best selectivity for the hA2A AR while the 5-benzylamino-substituted 5 displayed the best combined hA2A (Ki = 123 nM) and A1 AR affinity (Ki = 25 nM). The 5-phenethylamino moiety (compound 6) achieved nanomolar affinity (Ki = 11 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.[Formula: see text]. | |
| Digital Object Identifier (DOI): | 10.1080/14756366.2016.1247060 | |
| Handle: | http://hdl.handle.net/11392/2367659 | |
| Appare nelle tipologie: | 03.1 Articolo su rivista |
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