Modifications on the amino-3,5-dicyanopyridine core to obtain multifaceted adenosine receptor ligands with antineuropathic activity
| Autor: | Lorenzo Di Cesare Mannelli, Andrea Spinaci, Marta Menicatti, Elena Lucarini, Silvia Pasquini, Fabrizio Vincenzi, Marco Betti, Carla Ghelardini, Vittoria Colotta, Matteo Falsini, Flavia Varano, Gianluca Bartolucci, Daniela Catarzi, Diego Dal Ben, Katia Varani |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Male
Receptor Adenosine A2A Molecular model Stereochemistry CHO Cells Ligands Receptor Adenosine A2B Binding Competitive 01 natural sciences Mice 03 medical and health sciences chemistry.chemical_compound Economica Cricetulus G protein-coupled receptors Sulfanyl Cricetinae Drug Discovery Purinergic P1 Receptor Agonists Animals Humans Inverse agonist 030304 developmental biology neuropathic pain 0303 health sciences G protein-coupled receptors adenosine receptor ligands aminopyridine-3 5-dicarbonitriles ligand-adenosine receptor modeling studies neuropathic pain 5-dicarbonitriles Receptor Adenosine A1 Chemistry Antagonist amino-3 5-dicyanopyridines adenosine receptors neuropathic pain ligand-adenosine receptor modeling studies Adenosine receptor 0104 chemical sciences 010404 medicinal & biomolecular chemistry Purinergic P1 Receptor Antagonists adenosine receptor ligands Neuralgia Molecular Medicine Chemical stability aminopyridine-3 Caffeine Protein Binding |
| Popis: | A new series of amino-3,5-dicyanopyridines (1–31) was synthesized and biologically evaluated in order to further investigate the potential of this scaffold to obtain adenosine receptor (AR) ligands. In general, the modifications performed have led to compounds having high to good human (h) A1AR affinity and an inverse agonist profile. While most of the compounds are hA1AR-selective, some derivatives behave as mixed hA1AR inverse agonists/A2A and A2B AR antagonists. The latter compounds (9–12) showed that they reduce oxaliplatin-induced neuropathic pain by a mechanism involving the alpha7 subtype of nAchRs, similar to the nonselective AR antagonist caffeine, taken as the reference compound. Along with the pharmacological evaluation, chemical stability of methyl 3-(((6-amino-3,5-dicyano-4-(furan-2-yl)pyridin-2-yl)sulfanyl)methyl)benzoate 10 was assessed in plasma matrices (rat and human), and molecular modeling studies were carried out to better rationalize the available structure–activity relationships. |
| Databáze: | OpenAIRE |
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