Design and characterization of superpotent bivalent ligands targeting oxytocin receptor dimers via a channel-like structure
Open accessAbstract
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 analogues with a well-defined spacer length (∼25 Å) 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.
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- Authors
- Busnelli, M., Kleinau, G., Muttenthaler, M., Stoev, S., Manning, M., Bibic, L., Howell, L. A., McCormick, P. J., Di Lascio, S., Braida, D., Sala, M., Rovati, G. E., Bellini, T., & Chini, B.
- Affiliations
- University of Milan (IT)
- Charité – Universitätsmedizin Berlin (DE)
- The University of Queensland (AU)
- University of Toledo (US)
- University of East Anglia , , Norwich Research Park , ,
- University of East Anglia (GB)
- Università degli Studi di Milano , , ,
- CNR, Institute of Neuroscience , ,
- Corresponding author
- Chini, Bice
- ORCID
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2016-07-15
- Volume
- 59
- Issue
- 15
- Pages
- 7152-7166
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2466189304
- Cited by
- 67
- References
- 68
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 6 · 2023: 7 · 2022: 5 · 2021: 7 · 2020: 11 · 2019: 6 · 2018: 8 · 2017: 9 · 2016: 1
- FWCI
- 4.13
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Journal of Medicinal Chemistry (publishedVersion, other-oa)
- PubMed (publishedVersion)
- UEA Digital Repository (University of East Anglia) (acceptedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- Queen Mary Research Online (Queen Mary University of London) (submittedVersion, other-oa)
- Funders
- National Institute of General Medical Sciences (GM-25280)
- Directorate-General for Research and Innovation (254897)
- Biotechnology and Biological Sciences Research Council (MCCORMICK_U15DTP1)
- Australian Research Council (DE150100784)
- Deutsche Forschungsgemeinschaft (KL2334/2-2)
- Fondazione Telethon (GGP12207)
- Else Kröner-Fresenius-Stiftung (2014_A114)
- Consiglio Nazionale delle Ricerche (18099/RCC)
- Fondazione Umberto Veronesi (NA)
- Seventh Framework Programme (2013-BP-B-00109)
- Regione Lombardia (18099/RCC)
- Departament d'Economia i Coneixement, Generalitat de Catalunya (NA)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Keywords
- oxytocin receptor, bivalent ligands, receptor dimerization, G protein signaling, social behavior, zebrafish, mice, neurodevelopmental disorders, mental illness
- MeSH terms
- Animals, Dose-Response Relationship, Drug, Humans, Ligands, Models, Molecular, Molecular Conformation, Oxytocin, Structure-Activity Relationship, Drug Design, Receptors, Oxytocin, Dimerization, Mice, HEK293 Cells
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