The oxytocin receptor (OTR) is a G protein-coupled receptor (GPCR) involved in various physiological functions, including reproduction and social behaviour.[1] It is a therapeutic target for disorders such as cancer, pain, and autism.[2] Interactions between OTR and other GPCRs, specifically the Dopamine D2 receptor (D2R), were discovered. OTR-D2R heterodimers exist in different brain regions, adding another layer of complexity to the functional network of OTR.[3] Understanding the levels of OTR expression across different tissues and the functional relevance of dimer formation remains elusive due to a lack of specific antibodies and functional probes to investigate these aspects.
Over the last few years, we have actively addressed these shortcomings and present now the design, synthesis, pharmacological evaluation, and experimental application of innovative new tools aimed at investigating the OTR signalling system. Using a combination of solid-phase peptide synthesis and organic chemistry, we developed potent and selective peptide tracers for OTR detection and activation. We optimised these probes to maximise specificity and application scope, resulting in ultrabright, fixable probes with over 100-fold OTR selectivity. Moreover, we developed potent heterobivalent ligands targeting the OTR-D2R heterodimers. We successfully applied them in vitro, ex vivo and in vivo applications, including confocal microscopy and FACS.
In the upcoming stages of our research, we will conduct pharmacological assays using the prepared heterobivalent ligands in the context of OTR-D2R heterodimers aiming to unravel the effects of dimerization on elicited biological responses. This will provide valuable insights into the physiological relevance of OTR-D2R dimerization. Through our molecular tools, we anticipate unprecedented resolution in determining the spatial distribution of OTR and advancing the understanding of OTR's interaction with other receptors and its intricate roles in health and disease. Ultimately, this knowledge may pave the way for new therapeutic strategies targeting OTR, benefiting patients affected by various disorders.