Position 4 analogues of [deamino-Cys(1)] arginine vasopressin exhibit striking species differences for human and rat V-2/V-1b receptor selectivity

摘要

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[IIe(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 VIb receptor. Furthermore, peptides 1-4 exhibit high selectivities for the human VIb receptor with respect to the Via, 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 at., 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.