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...
Saved in:
Published in | Journal of medicinal chemistry Vol. 50; no. 18; pp. 4482 - 4492 |
---|---|
Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
WASHINGTON
American Chemical Society
06.09.2007
Amer Chemical Soc |
Subjects | |
Online Access | Get full text |
Cover
Loading…
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 |