O-linked melatonin dimers as bivalent ligands targeting dimeric melatonin receptors

• Published in: Bioorganic chemistry Vol. 85; pp. 349 - 356
• Main Authors: Karamitri, Angeliki, Sadek, Mirna S., Journé, Anne-Sophie, Gbahou, Florence, Gerbier, Romain, Osman, Mai B., Habib, Samy A.M., Jockers, Ralf, Zlotos, Darius P.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-04-2019
• Subjects: beta-Arrestins - metabolism; Bioluminescence Resonance Energy Transfer Techniques; Bivalent ligands; BRET; Cyclic AMP - metabolism; Drug Inverse Agonism; HEK293 Cells; Humans; Inverse agonist; Ligands; Melatonin; Melatonin - analogs & derivatives; Melatonin - metabolism; Melatonin - pharmacology; Molecular Structure; MT1 receptors; MT2 receptors; Protein Multimerization - drug effects; Receptor, Melatonin, MT1 - agonists; Receptor, Melatonin, MT1 - metabolism; Receptor, Melatonin, MT2 - agonists; Receptor, Melatonin, MT2 - metabolism; BRET; Melatonin; Bivalent ligands; MT1 receptors; MT2 receptors; Inverse agonist; MT receptors
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2019.01.004

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•Bivalent ligands 3a-e increase BRET signals of MT1 dimers up to 3-fold vs. control 4.•3a-e do not change BRET signals at MT2 dimers compared to monomeric control 4.•3c (20 atoms spacer) induces the strongest BRET change at MT1 dimeric receptors.•4: full MT1/MT2 agonist; 3c: no effect on cAMP conc. at MT1, inverse MT2 agonist.•4 and 3c are partial agonists in the β-arrestin assay at MT1 and MT2 receptors.
A series of dimeric melatonin analogues 3a-e obtained by connecting two melatonin molecules through the methoxy oxygen atoms with spacers spanning 16–24 atoms and the agomelatine dimer 7 were synthesized and characterized in 2-[125-I]-iodomelatonin binding assays, bioluminescence resonance energy transfer (BRET) experiments, and in functional cAMP and β-arrestin recruitment assays at MT1 and MT2 receptors. The binding affinity of 3a-e generally increased with increasing linker length. Bivalent ligands 3a-e increased BRET signals of MT1 dimers up to 3-fold compared to the monomeric control ligand indicating the simultaneous binding of the two pharmacophores to dimeric receptors. Bivalent ligands 3c and 7 exhibited important changes in functional properties on the Gi/cAMP pathway but not on the β-arrestin pathway compared to their monomeric counterparts. Interestingly, 3c (20 atoms spacer) shows inverse agonistic properties at MT2 on the Gi/cAMP pathway. In conclusion, these findings indicate that O-linked melatonin dimers are promising tools to develop signaling pathway-based bivalent melatonin receptor ligands.