Potent V2/V(1a) vasopressin antagonists with C-terminal ethylenediamine- linked retro-amino acids

Article abstract of DOI:10.1021/jm00099a018

We report the solid-phase synthesis and antagonistic potencies of 25 analogues (1-25) of [1-(β-mercapto-β,β-pentamethylenepropionic acid),2-O- ethyl-D-tyrosine,4-valine]arginine-vasopressin (d(CH₂)₅D-Tyr(Et)²-VAVP) (A) and of the related Ile⁴ (D) and [D-Phe²,Ile⁴] (E) analogues, potent antagonists of the antidiuretic (V₂-receptor) and of the vasopressor (V(1a)- receptor) responses to arginine-vasopressin (AVP). Six of these peptides (1, 13, 17, 19, 21, and 23) have the Pro-Arg-Gly-NH₂ tripeptide side chain fully or partially replaced or extended by ethylenediamine (Eda). The remaining 19 peptides have L- or D-amino acids retrolinked to these six C-terminal Eda peptides. Peptides 1, 13, 17, and 19 all have the ring structure of (A). Their side-chain structures are as follows: 1, Eda; 13, Pro-Eda; 17, Pro-Arg- Eda; 19, Arg-Gly-Eda. Peptide 21 is the Pro-Arg-Eda analogue of D; peptide 23 is the Pro-Arg-Gly-Eda analogue of E. Peptide 2 is the retro-Arg analogue of 1. Its side-chain structure is Eda←Arg. Peptides 3-6 are analogues of 2 which have the D-Tyr-(Et)² residue replaced by L-Tyr(Et)² (3), D-Phe² (4), D-Ile² (5), or D-Leu² (6), respectively. Peptides 7-12 are analogues of 2 which have the C-terminal retro-Arg replaced in retrofashion by D-Arg (7), Gly (8), Orn (9), D-Orn (10), D-Lys (11), or Arg-Arg (12). Peptides 14-16 have D-Orn (14), D-Lys (15), and D-Arg (16) retrosubstituted to peptide 13. Peptides 18, 20, and 22 are the retro-Arg-substituted analogues of 17, 19, and 21, respectively. Peptides 24 and 25 have Val and D-Val in retrolinkage with 23, respectively. All 25 peptides were examined for agonistic and antagonistic potencies in AVP V₂/V(1a) assays. With the exception of peptides 5 and 6, all exhibit potent anti-V(1a) antagonism, with anti-V(1a) pA₂ values in the range 7.64-8.33. Peptides 1-25 exhibit the following anti- V₂ pA₂ values: 1, 7.07 ± 0.05; 2, 7.54 ± 0.10; 3, 6.39 ± 0.04; 4, 6.91 ± 0.06; 5, ~5.8; 6, <5.5; 7, 7.95 ± 0.10; 8, 6.59 ± 0.02; 9, 7.55 ± 0.03; 10, 7.24 ± 0.05; 11, 7.76 ± 0.07; 12, 7.61 ± 0.09; 13, 7.64 ± 0.07; 14, 7.92 ± 0.05; 15, 7.78 ± 0.09; 16, 7.92 ± 0.05; 17, 7.79 ± 0.04; 18, 7.68 ± 0.06; 19, 8.03 ± 0.08; 20, 7.87 ± 0.05; 21, 8.00 ± 0.12; 22, 8.10 ± 0.09; 23, 8.10 ± 0.10; 24, 8.10 ± 0.08; 25, 8.09 ± 0.09. Comparison of the anti-V₂ potencies of peptides 1-6 clearly shows the superiority of the D-Tyr(Et)² substitution in leading to retention and enhancement of V₂ antagonism in this series. With only one exception (peptide 8), the retromodified peptides exhibit either full retention and in a number of cases (2, 7, 9-12, 14, and 16) a 1.5-7.5-fold enhancement of V₂ antagonism compared to their respective parent C-terminal Eda peptides. The retro-Arg- substituted Ile⁴ peptide 22 exhibits a 2-fold enhancement of anti-V₂ potency relative to its Val⁴ counterpart 18. The retromodified peptides 24 and 25, which possess extensions at the C-terminal, also exhibit good retention of V₂ antagonism. Many of these retrosubstituted peptides are as potent as the most potent V₂ antagonists reported to date. Some of these may be orally active. These findings point to the usefulness of Eda retromodifications in the design of AVP antagonists. Furthermore they provide useful clues to the design of (a) more potent and selective AVP antagonists and (b) novel photoaffinity and radioiodinated ligands as probes of AVP receptors.