Pharmacological and Physiological Characterization of d[Leu4, Lys8]Vasopressin, the First V1b-Selective Agonist for Rat Vasopressin/Oxytocin Receptors

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 ...