PUBLICATION
Design and characterization of superpotent bivalent ligands targeting oxytocin receptor dimers via a channel-like structure
- Authors
- Busnelli, M., Kleinau, G., Muttenthaler, M., Stoev, S.B., Manning, M., Bibic, L., Howell, L.A., McCormick, P.J., Di Lascio, S., Braida, D., Sala, M., Rovati, G.E., Bellini, T., Chini, B.
- ID
- ZDB-PUB-160716-2
- Date
- 2016
- Source
- Journal of medicinal chemistry 59(15): 7152-66 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals
- Dimerization
- Dose-Response Relationship, Drug
- Drug Design*
- HEK293 Cells
- Humans
- Ligands
- Mice
- Models, Molecular
- Molecular Conformation
- Oxytocin/chemical synthesis
- Oxytocin/chemistry
- Oxytocin/pharmacology*
- Receptors, Oxytocin/agonists*
- Structure-Activity Relationship
- PubMed
- 27420737 Full text @ J. Med. Chem.
Citation
Busnelli, M., Kleinau, G., Muttenthaler, M., Stoev, S.B., Manning, M., Bibic, L., Howell, L.A., McCormick, P.J., Di Lascio, S., Braida, D., Sala, M., Rovati, G.E., Bellini, T., Chini, B. (2016) Design and characterization of superpotent bivalent ligands targeting oxytocin receptor dimers via a channel-like structure. Journal of medicinal chemistry. 59(15):7152-66.
Abstract
Dimeric/oligomeric states of G-protein coupled receptors have been difficult to target. We report here bivalent ligands consisting of two identical oxytocin-mimetics that induce a three order magnitude boost in G-protein signaling of oxytocin receptors (OTRs) in vitro and a 100- and 40-fold gain in potency in vivo in the social behavior of mice and zebrafish. Through receptor mutagenesis and interference experiments with synthetic peptides mimicking transmembrane helices (TMH), we show that such superpotent behavior follows from the binding of the bivalent ligands to dimeric receptors based on a TMH1-TMH2 interface. Moreover, in this arrangement, only the analogs with a well defined spacer length (~25 Ǻ) precisely fit inside a channel-like passage between the two protomers of the dimer. The newly discovered oxytocin bivalent ligands represent a powerful tool for targeting dimeric OTR in neurodevelopmental and psychiatric disorders and, in general, provide a framework to untangle specific arrangements of G-protein coupled receptor dimers.
Genes / Markers
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Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
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