Synthesis of specific bivalent probes that functionally interact with 5-HT(4) 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-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.
Russo
Olivier
O
Université Paris-Sud, Faculté de Pharmacie, IFR141, UMR-S769, Châtenay-Malabry, F-92296, Inserm, U567, France.
Berthouze
Magali
M
Giner
Mireille
M
Soulier
Jean-Louis
JL
Rivail
Lucie
L
Sicsic
Sames
S
Lezoualc'h
Frank
F
Jockers
Ralf
R
Berque-Bestel
Isabelle
I
D062365:Aminobenzoates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000096:biosynthesis; D019281:Dimerization; D004735:Energy Transfer; D006801:Humans; D008024:Ligands; D049449:Luminescence; D008958:Models, Molecular; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D044422:Receptors, Serotonin, 5-HT4 / Q000737:chemistry / Q000187:drug effects*; D058828:Serotonin 5-HT4 Receptor Agonists; D013329:Structure-Activity Relationship; D062366:para-Aminobenzoates
C117947:2-piperidinoethyl 4-amino-5-chloro-2-methoxybenzoate; D062365:Aminobenzoates; D008024:Ligands; D010880:Piperidines; D058828:Serotonin 5-HT4 Receptor Agonists; D062366:para-Aminobenzoates; D044422:Receptors, Serotonin, 5-HT4; D000242:Cyclic AMP