title: Position 4 analogues of [deamino-Cys(1)] arginine vasopressin exhibit striking species differences for human and rat V(2)/V(1b) 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.
authors.affiliation: Institut de Génomique Fonctionnelle, UMR5203-CNRS, U661-INSERM, Université Montpellier I & II, 141 rue de la Cardonille, 34094 Montpellier Cedex 5, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Guillon
authors.forename: Ana
authors.initials: A
authors.lastname: Pena
authors.forename: Brigitte
authors.initials: B
authors.lastname: Murat
authors.forename: Sylvain
authors.initials: S
authors.lastname: Derick
authors.forename: Miguel
authors.initials: M
authors.lastname: Trueba
authors.forename: Maria A
authors.initials: MA
authors.lastname: Ventura
authors.forename: Hazel H
authors.initials: HH
authors.lastname: Szeto
authors.forename: Nga
authors.initials: N
authors.lastname: Wo
authors.forename: Stoytcho
authors.initials: S
authors.lastname: Stoev
authors.forename: Ling Ling
authors.initials: LL
authors.lastname: Cheng
authors.forename: Maurice
authors.initials: M
authors.lastname: Manning
mesh_terms: D000818:Animals; D050034:Antidiuretic Agents / Q000819:agonists / Q000737:chemistry / Q000494:pharmacology; D001127:Arginine Vasopressin / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D005260:Female; D006801:Humans; D010120:Oxytocics / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017483:Receptors, Vasopressin / Q000819:agonists / Q000737:chemistry* / Q000187:drug effects; D013045:Species Specificity; D013329:Structure-Activity Relationship; D014662:Vasoconstrictor Agents / Q000737:chemistry / Q000494:pharmacology
chemical_list: D050034:Antidiuretic Agents; D010120:Oxytocics; D017483:Receptors, Vasopressin; D014662:Vasoconstrictor Agents; D001127:Arginine Vasopressin