Résumé
Recently, we synthesized and characterized the first selective V1b vasopressin (VP)/oxytocin receptor agonist, d[Cha4]arginine vasopressin. However, this agonist was only selective for the human receptors. We thus decided to design a selective V1b agonist for the rodent species. We started from previous observations showing that modifying [deamino1,Arg8]VP in positions 4 and 8 altered the rat VP/oxytocin receptor selectivity. We synthesized a series of 13 [deamino1,Arg8]VP analogs modified in positions 4 and 8. Among them, one seemed very promising, d[Leu4, Lys8]VP. In this paper, we describe its pharmacological and physiological properties. This analog exhibited a nanomolar affinity for the rat, human, and mouse V1b VP receptors and a strong V1b selectivity for the rat species. On AtT20 cells stably transfected with the rat V1b receptor, d[Leu4, Lys8]VP behaved as a full agonist on both phospholipase C and MAPK assays. Additional experiments revealed its ability to induce the internalization of enhanced green fluorescent protein-tagged human and mouse V1b receptors as expected for a full agonist. Additional physiological experiments were performed to further confirm the selectivity of this peptide. Its antidiuretic, vasopressor, and in vitro oxytocic activities were weak compared with those of VP. In contrast, used at low doses, its efficiency to stimulate adrenocorticotropin or insulin release from mouse pituitary or perfused rat pancreas, respectively, was similar to that obtained with VP. In conclusion, d[Leu4, Lys8]VP is the first selective agonist available for the rat V1b VP receptor. It will allow a better understanding of V1b receptor-mediated effects in rodents.