Position 4 analogues of [deamino-Cys1] arginine vasopressin exhibit striking species differences for human and rat V2/V1b receptor selectivity

Abstract

Arginine vasopressin (AVP) mediates a wide variety of biological actions by acting on three distinct G-protein coupled receptors, termed V(1a) (vascular), V(1b) (pituitary) and V(2) (renal). It also binds to the oxytocin (OT) receptor. As part of a program aimed at the design of selective agonists for the human V(1b) receptor, we recently reported the human V(1b), V(1a), V(2) and OT receptor affinities of the following position 4 substituted analogues of [deamino-Cys(1)] arginine vasopressin (dAVP)-(1) d[Leu(4)]AVP, (2) d[Orn(4)]AVP, (3) d[Lys(4)]AVP, (4) d[Har(4)]AVP, (5) d[Arg(4)]AVP, (6) d[Val(4)]AVP, (7) d[Ala(4)]AVP, (8) d[Abu(4)]AVP, (9) d[Nva(4)]AVP, (10) d[Nle(4)]AVP, (11) d[Ile(4)]AVP, (12) d[Phe(4)]AVP, (13) d[Asn(4)]AVP, (14) d[Thr(4)]AVP: (15) d[Dap(4)]AVP. With the exception of Nos. 7 and 12, all peptides exhibit very high affinities for the human V(1b) receptor. Furthermore, peptides 1-4 exhibit high selectivities for the human V(1b) receptor with respect to the V(1a), V(2) and OT receptors and, with d[Cha(4)]AVP, in functional tests, are the first high affinity selective agonists for the human V(1b) receptor (Cheng LL et al., J. Med. Chem. 47: 2375-2388, 2004). We report here the pharmacological properties of peptides 1-4, 5 (from a resynthesis), 7, 9-13, 15 in rat bioassays (antidiuretic, vasopressor and oxytocic) (in vitro: no Mg(++)) with those previously reported for peptides 5, 6, 8, 14. We also report the rat V(1b), V(1a), V(2) and OT receptor affinities of peptides 1-5 and the rat V(2) receptor affinities for peptides: 7-15.The antidiuretic activities in units/mg of peptides 1-15, are: 1=378; 2=260; 3=35; 4=505; 5=748; 6=1150; 7=841; 8=1020; 9=877; 10=1141; 11=819, 12=110; 13=996; 14=758; 15=1053. Peptides 1-4 exhibit respectively the following rat and human (in brackets) V(2) receptor affinities: 1=3.1 nm (245 nm); 2=3.4 nm (1125 nm); 3=24.6 nm (11,170 nm); 4=0.6 nm (1386 nm). Their rat V(1b) receptor affinities are 1=0.02 nm; 2=0.45 nm; 3=9.8 nm; 4=0.32 nm. Their rat V(1a) receptor affinities are 1=1252 nm; 2=900 nm; 3=1478 nm; 4=32 nm. Their rat oxytocin (OT) receptor affinities are 1=481 nm; 2=997 nm; 3=5042 nm; 4=2996 nm. All four peptides have high affinities and selectivities for the rat V(1b) receptor with respect to the rat V(1a) and OT receptors. However, in contrast to their high selectivity for the human V(1b) receptor with respect to the human V(2) receptor, they are not selective for the V(1b) receptor with respect to the V(2) receptor in the rat. These findings confirm previous observations of profound species differences between the rat and human V(2) receptors. Peptides 1-4 are promising leads to the design of the first high affinity selective agonists for the rat V(1b) receptor.

Differential Coupling of the Vasopressin V1b Receptor through Compartmentalization within the Plasma Membrane

“…In both cases, high concentrations of d [Cha 4 ]AVP were necessary to elicit the response ( Fig. 4B; Table 2), even though the affinity of this compound for the rat V 1b receptor is known to be 1.4 nM in CHO cells (Guillon et al, 2006). Both curves exhibited a slope factor of around 1 and lower maximal stimulation levels than those observed with AVP (Ϫ18 and Ϫ59% for the IP and cAMP pathways, respectively; Table 2).…”

“…To address whether the two signaling pathways exhibit different pharmacological properties, we examined the effects on both pathways of one specific nonpeptidic V 1b antagonist, SSR149415 (Serradeil-Le Gal et al, 2002), and two peptidic agonists of AVP, arginine-vasotocin (AVT), the nonmammalian vertebrate ortholog of AVP, and d [Cha 4 ]AVP, a specific V 1b receptor agonist (Guillon et al, 2006). IP 1 and cAMP accumulations in V 1b -transfected CHO cells stimulated with increasing AVP concentrations was studied without or with increasing amounts of SSR149415.…”

Terlipressin, a provasopressin drug exhibits direct vasoconstrictor properties: Consequences on heart perfusion and performance*

“…previously described for the vasopressin receptor family (27). Terlipressin vasoconstrictive effect may depends on species differences or variation in vasopressin receptors density from one organ to another.…”

Pharmacology and selectivity of various natural and synthetic bombesin related peptide agonists for human and rat bombesin receptors differs

“…Recently this has changed with the widespread interest in taking advantage of Bn receptor overexpression in various human tumors for Bn receptor-mediated imaging and/or cytotoxicity, using primarily Bn receptor agonists [66,67,95]. However, the extrapolation of pharmacological/signaling results from nonhuman studies to human tissues may be problematic, because a number of studies have shown with Bn receptors, as well as a number of other peptide G protein-coupled receptors [VPAC, tachykinins, melanocortin, vasopressin, endothelin], important differences may exist in pharmacology/cell signaling between these receptors on humans and nonhuman tissues, as well as on cells from different animal species [3,13,23,27,35,40,68,79,88,92,93]. With a number of these receptors there are especially important differences between human and rodent species (rat, mouse), which are the most widely used laboratory animals and whose receptors are frequently characterized pharmacologically, such as with Bn receptors [23,27–29,35,40,68,79,88,92,93].…”

“…This has led to a reliance on results from animal studies, particularly from rodents for optimum pharmacological design. This approach can lead to inaccurate conclusions, because with a number of different G protein coupled receptors, including Bn receptors, there are reports of important species differences, especially between human and rodent receptors, on agonist receptor interaction/activation [23,27,29,35,40,68,88,92,93]. Similarly, high densities of receptors, as frequently occur with transfected cell systems, including with Bn receptors [87], can have marked effects on agonist receptor activation/interaction, leading to conclusions which may not be applicable to native cells with lower Bn-receptor densities, as seen in vivo .…”