Synthesis and structure-activity investigation of novel vasopressin hypotensive peptide agonists

We report the solid phase synthesis and vasodepressor potencies of the nove l hypotensive peptide [1(-beta-mercapto-beta,beta-pentamethylene propionic acid)-2-O-ethyl-D-tyrosine, 3-arginine, 4-valine] arginine vasopressin, d(C H2)(5)[D-Tyr(Et)(2), Arg(3), Val(4)]AVP (A), its related Lys(3) (B), Tyr-NH 29 (C), [Lys(3), Tyr-NH29] (D) analogs and in a preliminary structure-activ ity study of positions 2-4 and 7-9, 24 analogs (1-24) of A-C. Peptides 1-6, 9-14 have the following single substituents at positions 2, 3, 4, 8 and 9 in (A): 1, D-Tyr(Me)(2);: 2, L-Tyr(Et)(2); 3, Orn(3); 4, N-Me-Arg(3); 5, Gl u(3); 6, Arg(4); 9, D-Arg(8); 10, Eda(9); 11, Arg-NH29; 12, Ala-NH29; 13, d esGly(9); 14, desGly-NH29. Peptides 15 and 16 are analogs of B which posses s the following single modifications: 15, Arg-NH29; 16, desGly(9). Peptides 7 and 8 are analogs of (C) with the following single modification: 7, Gln( 4); 8, Lys(8). Peptides 17-24 are analogs of A possessing the following mul tiple modifications: 17, [Sar(7), Eda(9)]; 18, [Arg(7), Eda(9)]; 19, [Arg(7 ), Eda(9) <-- Tyr(10)]; 20, [Arg(4), Arg-NH29]; 21, [Ile(4), desGly(9)]; 22 , [Arg(4), desGly(9)]: 23, [Arg(7), desGly(9)]; 24, [Arg(7), Lys(8), desGly (9)]. All 24 new peptides were evaluated for agonistic and antagonistic act ivities in in vivo antidiuretic (V-2-receptor), vasopressor (V-1a-receptor) and in in vitro (no Mg2+) oxytocic (OT-receptor) assays and like the paren t peptides (A-D) (Chan et al. Br. J. Pharmacol. 1998; 125; 803-811) were fo und to exhibit no or negligible activities in these assays. Vasodepressor p otencies were determined in anesthetized male rats with baseline mean arter ial blood pressure maintained at 110-120 mmHg. The effective dose (ED), in mu g 100 g(-1) i.v., required to produce a vasodepressor response of 5 cm(2 ), area under the vasodepressor response curve (AUC) during the 5-min perio d following the injection of the test peptide, was determined. Therefore, t he EDs measure the relative vasodepressor potencies of the hypotensive pept ides. The following ED values were obtained for A-D and for peptides 1-24: A, 4.66; B, 5.75; C, 10.56; D, 11.60; 1, similar to 20; 2, similar to 30; 3 , 6.78; 4, non-detectable (ND); 5, ND; 6, similar to 32; 7, ND; 8, 8.67; 9, ND; 10, 2.43: 11, 3.54; 12, 10.57; 13, 4.81; 14, ND; 15, 4.47; 16, 9.78; 1 7, 5.72; 18, 1.10: 19, 1.05; 20, 10.41; 21, 9.13; 22, similar to 33; 23, 3. 01; 24, 1.71. A is clearly the most potent of the four original hypotensive peptides A-D. These data provide insights to which modification of A enhan ce, retain or abolish hypotensive potencies. Six of the new hypotensive pep tides are significantly more potent than A. These are peptides 10, 11, 18, 19, 23 and 24. Peptide 19, a radioiodinatable ligand, is ten times more pot ent than C or D. The Gln(4) modification of C and the N-Me-Arg(3), Glu(3), D-Arg(8) and desGly-NH29 modifications of A abolished hypotensive potency. By contrast, the Eda(9), Arg-NH29, [Sar(7), Eda(9)], [Arg(7), Eda(9) <-- Ty r(10)], [Arg(7), desGly(9)], [Arg(7), Lys(8), desGly(9)] modifications of A all led to enhancements of hypotensive potency. This initial structure-act ivity exploration provides useful clues to the design of (a) more potent va sodepressor peptides and (b) high affinity radioiodinatable ligands for the putative AVP vasodilating receptor. Some of the peptides here may be of va lue as pharmacological tools for studies on the complex cardiovascular acti ons of AVP and may lead to the development of a new class of anti-hypertens ive agents. Copyright (C) 1999 European Peptide Society and John Wiley gr S ons, Ltd.