Oxytocin (OT) and arginine-vasopressin (AVP) were the first peptides to be discovered, synthesized and characterized over 60 years ago, yet today we still lack a complete toolbox of selective agonists and antagonists for the four known receptor subtypes. Considering the ubiquitous presence of OT and AVP receptors in the periphery and CNS in addition to their role in a multitude of important physiologically processes, it is central to have a plethora of selective ligands for concluding studies. Ideally, these ligands should not only be selective, but should also preserve their selectivity in different species allowing for translational studies important for drug development. While there has been great medicinal chemistry conducted over the last decades on shaping such ligands, we decided to take a different approach, taking advantage of the fact that the OT/AVP signaling system has been well preserved in the kingdom of life for millions of years, and started exploring these natural sources for novel ligands.
The venom of the cone snail and the genome of social ants turned out to be such natural sources, both yielding excellent lead compounds for the design of receptor selective ligands. Here we would like to discuss the rationale behind our approaches, the techniques involved and how structure-activity relationship studies of these lead peptides influenced our ligand design, eventually leading to the identification of an agonist to antagonist switch for AVP, the development of a selective hOTR agonist that retained its selectivity profile in mice and humans, the identification of exceptionally potent peptides for zebra fish social studies and the development of stable ligands towards the treatment of chronic abdominal pain.