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Position 4 analogues of [deamino‐Cys 1 ] arginine vasopressin exhibit striking species differences for human and rat V 2 /V 1b receptor selectivity
Author(s) -
Guillon Gilles,
Pena Ana,
Murat Brigitte,
Derick Sylvain,
Trueba Miguel,
Ventura Maria A.,
Szeto Hazel H.,
Wo Nga,
Stoev Stoytcho,
Cheng Ling Ling,
Manning Maurice
Publication year - 2006
Publication title -
journal of peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 66
eISSN - 1099-1387
pISSN - 1075-2617
DOI - 10.1002/psc.710
Subject(s) - vasopressin , arginine vasopressin receptor 1b , receptor , arginine , arginine vasopressin receptor 2 , vasopressin receptor , oxytocin , endocrinology , chemistry , medicine , neuropeptide , amino acid , biochemistry , biology
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. Copyright © 2005 European Peptide Society and John Wiley & Sons, Ltd.