Multivalent ligands for the serotonin 5-HT4 receptor
| Autor: | Marco Paolino, Maurizio Anzini, Laura Mennuni, Paola Molinari, Francesco Makovec, Andrea Cappelli, Federica Castriconi, Maria Sbraccia, Tommaso Costa, Gianfranco Caselli, Chiara Sabatini, Marco Lanza, Alessandro Donati, Germano Giuliani |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Pharmacology Molecular model Chemistry Stereochemistry Organic Chemistry Pharmaceutical Science 5-HT4 receptor Ligand (biochemistry) Biochemistry Partial agonist 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology Membrane Drug Discovery Molecular Medicine Receptor Ethylene glycol 5-HT receptor |
| Popis: | 5-HT4 receptors are known to form constitutive dimers in membranes. To explore whether multivalency can enhance ligand interactions and/or efficacy in 5-HT4 receptors, the structure of the partial agonist ML10302 was modified with oligo(ethylene glycol) chains, thus generating, by a gradual approach, short and long tethered bivalent or tetravalent ligands and the corresponding spanner-linked monovalent controls. Both bivalent and tetravalent ligands displayed a 10–20-fold increase in binding affinity compared to appropriate controls, but no multivalent ligand showed greater binding energy than ML10302 itself. Furthermore, the direct assessment of receptor–Gs interaction and studies of cAMP signalling indicated that multivalency does not enhance the efficacy of ML10302. |
| Databáze: | OpenAIRE |
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