Synthesis of specific bivalent probes that functionally interact with 5-HT(4) receptor dimers
| Autor: | Mireille Giner, Sames Sicsic, Isabelle Berque-Bestel, Olivier Russo, Magali Berthouze, Jean-Louis Soulier, Frank Lezoualc'h, Ralf Jockers, Lucie Rivail |
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| Rok vydání: | 2007 |
| Předmět: |
Models
Molecular Luminescence Molecular model medicine.drug_class Stereochemistry Dimer Carboxamide Ligands Chemical synthesis Bivalent (genetics) Cell Line chemistry.chemical_compound Radioligand Assay Serotonin 5-HT4 Receptor Agonists Structure-Activity Relationship Cricetulus Piperidines Cricetinae Drug Discovery medicine Cyclic AMP para-Aminobenzoates Animals Humans Aminobenzoates Ligand Monomer chemistry Energy Transfer Molecular Medicine Receptors Serotonin 5-HT4 Pharmacophore Dimerization |
| Zdroj: | Journal of medicinal chemistry. 50(18) |
| ISSN: | 0022-2623 |
| Popis: | G-protein-coupled receptor dimerization directs the design of new drugs that specifically bind to receptor dimers. Here, we generated a targeted series of homobivalent ligands for serotonin 5-HT(4) receptor (5-HT(4)R) dimers composed of two 5-HT(4)R-specific ML10302 units linked by a spacer. The design of spacers was assisted by molecular modeling using our previously described 5-HT(4)R dimer model. Their syntheses were based on Sonogashira-Linstrumelle coupling methods. All compounds retained high-affinity binding to 5-HT(4)R but lost the agonistic character of the monomeric ML10302 compound. Direct evidence for the functional interaction of both pharmacophores of bivalent ligands with the 5-HT(4)R was obtained using a bioluminescence resonance energy transfer (BRET) based assay that monitors conformational changes within 5-HT(4) dimers. Whereas the monovalent ML10302 was inactive in this assay, several bivalent derivatives dose-dependently increased the BRET signal, indicating that both pharmacophores functionally interact with the 5-HT(4) dimer. These bivalent ligands may serve as a new basis for the synthesis of potential drugs for 5-HT(4)-associated disorders. |
| Databáze: | OpenAIRE |
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