Synthesis and structure-activity relationship studies in serotonin 5-HT4 receptor ligands based on a benzo[de][2,6]naphthridine scaffold
| Autor: | Andrea Cappelli, Marco Lanza, Maria Sbraccia, Marco Paolino, Maria Cristina Menziani, Paola Molinari, Gianfranco Caselli, Tommaso Costa, Laura Mennuni, Giuseppe Campiani, Germano Giuliani, Francesca De Rienzo, Federica Castriconi, Maurizio Anzini, Chiara Sabatini |
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| Rok vydání: | 2013 |
| Předmět: |
Male
Models Molecular Intrinsic activity Stereochemistry Guinea Pigs G-protein coupled receptor Serotonin 5-HT4 receptor Crystallography X-Ray Ligands Synthesis Serotonin 5-HT4 Receptor Agonists Structure-Activity Relationship Drug Discovery Structure–activity relationship Animals Binding site Naphthyridines Receptor 5-HT4 receptor ligands G protein-coupled receptor Pharmacology Molecular modelling Dose-Response Relationship Drug Molecular Structure Chemistry Organic Chemistry General Medicine Docking (molecular) Serotonin Receptors Serotonin 5-HT4 |
| Zdroj: | European journal of medicinal chemistry. 82 |
| ISSN: | 1768-3254 |
| Popis: | A small series of serotonin 5-HT4 receptor ligands has been designed from flexible 2-methoxyquinoline compounds 7a,b by applying the conformational constraint approach. Ligands 7a,b and the corresponding conformationally constrained analogues 8a-g were synthesized and their interactions with the 5-HT4 receptor were examined by measuring both binding affinity and the ability to promote or inhibit receptor-G protein coupling. Ester derivative 7a and conformationally constrained compound 8b were demonstrated to be the most interesting compounds showing a nanomolar 5-HT4R affinity similar to that shown by reference ligands cisapride (1) and RS-23,597-190 (4). The result was rationalized by docking studies in term of high similarity in the binding modalities of flexible 7a and conformationally constrained 8b. The intrinsic efficacy of some selected ligands was determined by evaluating the receptor-G protein coupling and the results obtained demonstrated that the nature and the position of substituents play a critical role in the interaction of these ligands with their receptor. |
| Databáze: | OpenAIRE |
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