Synthesis of Specific Bivalent Probes That Functionally Interact with 5-HT4 Receptor Dimers

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-HT4 receptor (5-HT4R) dimers composed of two 5-HT4R-specific ML10302 units linked by a spacer. The design of...

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Published inJournal of medicinal chemistry Vol. 50; no. 18; pp. 4482 - 4492
Main Authors Russo, Olivier, Berthouze, Magali, Giner, Mireille, Soulier, Jean-Louis, Rivail, Lucie, Sicsic, Sames, Lezoualc'h, Frank, Jockers, Ralf, Berque-Bestel, Isabelle
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 06.09.2007
Amer Chemical Soc
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Summary: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-HT4 receptor (5-HT4R) dimers composed of two 5-HT4R-specific ML10302 units linked by a spacer. The design of spacers was assisted by molecular modeling using our previously described 5-HT4R dimer model. Their syntheses were based on Sonogashira−Linstrumelle coupling methods. All compounds retained high-affinity binding to 5-HT4R 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-HT4R was obtained using a bioluminescence resonance energy transfer (BRET) based assay that monitors conformational changes within 5-HT4R 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-HT4R dimer. These bivalent ligands may serve as a new basis for the synthesis of potential drugs for 5-HT4R-associated disorders.
Bibliography:istex:FDB97D1500477D1C14EEEBAA1D09DACE845290E0
ark:/67375/TPS-P72FT7VD-3
ISSN:0022-2623
1520-4804
DOI:10.1021/jm070552t