5,7-Disubstituted-[1,2,4]triazolo[1,5-a][1,3,5]triazines as pharmacological tools to explore the antagonist selectivity profiles toward adenosine receptors
| Autor: | Stefano Moro, Giampiero Spalluto, Stephanie Federico, Karl-Norbert Klotz, Antonella Ciancetta, Giorgia Pastorin, Nicola Porta, Barbara Cacciari, Sara Redenti |
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| Přispěvatelé: | Federico, Stephanie, Ciancetta, Antonella, Porta, Nicola, Redenti, Sara, Pastorin, Giorgia, Cacciari, Barbara, Klotz, Karl Norbert, Moro, Stefano, Spalluto, Giampiero |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Models
Molecular 0301 basic medicine Molecular model Pyrimidine Stereochemistry Molecular modeling NO Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Triazolo-triazine Drug Discovery Humans Structure–activity relationship Moiety Adenosine receptors G protein-coupled receptor Pharmacology Dose-Response Relationship Drug Molecular Structure Triazines Drug Discovery3003 Pharmaceutical Science Organic Chemistry Receptors Purinergic P1 Adenosine receptor Antagonist General Medicine Triazoles Structure activity relationship 030104 developmental biology Purinergic P1 Receptor Antagonists chemistry Antagonists G protein-coupled receptor Antagonists Molecular modeling Structure activity relationship Triazolo-triazine Adenosine receptors Selectivity |
| Popis: | The structure–activity relationship of new 5,7-disubstituted-[1,2,4]triazolo[1,5-a][1,3,5]triazines as adenosine receptors (ARs) antagonists has been explored. The introduction of a benzylamino group at C5 with a free amino group at C7 increases the affinity toward all the ARs subtypes (10: KihA1 = 94.6 nM; KihA2A = 1.11 nM; IC50hA2B = 2214 nM; KihA3 = 30.8 nM). Replacing the free amino group at C7 with a phenylureido moiety yields a potent and quite selective hA2A AR antagonist (14: hA2A AR Ki = 1.44 nM; hA1/hA2A = 216.0; hA3/hA2A = 20.6). This trend diverges from the analysis on the pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine series previously reported. With the help of an in silico receptor-driven approach, we have rationalized these observations and elucidated from a molecular point of view the role of the benzylamino group at C5 in determining affinity toward the hA2A AR. |
| Databáze: | OpenAIRE |
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