Oxytocin (OT) and vasopressin (AVP) receptors are part of a 600 million year old signalling system that is widely distributed in the kingdom of life. It is involved in many fundamental physiological functions including reproduction, water balance, pain and complex social interaction. We still have however no complete set of selective agonists/antagonists to delineate the physiological function of the four known receptor subtypes (OT, V1a, V1b, V2). Endogenous OT/AVP are unselective and high extracellular receptor subtype homology (~80%) combined with low inter-species receptor correlation significantly hampers molecular probe and therapeutic ligand development.
Breaking away from classical medicinal chemistry approaches, we started exploring natural sources and innovative chemistry to tackle above-mentioned challenges. Cone snail venom, plant extracts and genome mining of social ants provided excellent lead compounds with improved activity and selectivity. Ligand fine-tuning enabled us to create ligands that retained their selectivity profile across species. Receptor homology modelling and multivalent ligand design further added to our repertoire towards grafting a complete molecular toolbox. Here we present the techniques, innovative chemistry and SAR studies that yielded two selective OTR agonists, one V1aR antagonist, one V1bR agonist and a biased V1b/V2 agonist. These ligands already play an important role in dissecting the OT/AVP receptor subtype contribution in disorders such as irritable bowel syndrome, diabetes insipidus, breast cancer and autism.