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

Abstract

Recently, we synthesized and characterized the first selective V(1b) vasopressin (VP)/oxytocin receptor agonist, d[Cha(4)]arginine vasopressin. However, this agonist was only selective for the human receptors. We thus decided to design a selective V(1b) agonist for the rodent species. We started from previous observations showing that modifying [deamino(1),Arg(8)]VP in positions 4 and 8 altered the rat VP/oxytocin receptor selectivity. We synthesized a series of 13 [deamino(1),Arg(8)]VP analogs modified in positions 4 and 8. Among them, one seemed very promising, d[Leu(4), Lys(8)]VP. In this paper, we describe its pharmacological and physiological properties. This analog exhibited a nanomolar affinity for the rat, human, and mouse V(1b) VP receptors and a strong V(1b) selectivity for the rat species. On AtT20 cells stably transfected with the rat V(1b) receptor, d[Leu(4), Lys(8)]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 V(1b) 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[Leu(4), Lys(8)]VP is the first selective agonist available for the rat V(1b) VP receptor. It will allow a better understanding of V(1b) receptor-mediated effects in rodents.

Increase in Alzheimer's related markers preceeds memory disturbances: Studies in vasopressin-deficient Brattleboro rat

“…We found a small increase in the MAPK mRNA level in old rats, which was more pronounced in AVPdeficient animals. Signalisation cascade of AVP may include the MAPK pathway as well [44]. Although an elevated MAPK expression in old di/di rats seems to be contradictory, this is not the only pathway for AVP and many other molecules may manipulate the MAPK cascade.…”

Guide to Receptors and Channels (GRAC), 5th edition

“…YM087 display high affinity for both human V1a and V2 receptors (Tahara et al, 1998). d [Cha 4 ]AVP is selective only for the human and bovine V1b receptors (Derick et al, 2002) ]VP has high affinity for the rat V1b receptor (Pena et al, 2007).…”

Sustained Elevated Levels of Circulating Vasopressin Selectively Stimulate the Proliferation of Kidney Tubular Cells via the Activation of V2 Receptors

“…Rat kidney tissues from the cortex, outer medulla, and inner medulla were carefully dissected and treated for immunoblot analysis as previously described (25). Phosphorylated ERKs were revealed by using a 1:2000 dilution of mouse monoclonal antiphospho-ERK antibody (phospho-p44/42 MAPK Thr202/Tyr204; Cell Signaling Technology, Inc., Danvers, MA).…”