Potent V2/V1a vasopressin antagonists with C-terminal ethylenediamine-linked retro-amino acids.
We report the solid-phase synthesis and antagonistic potencies of 25 analogues (1-25) of [1-(beta-mercapto-beta,beta-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 (V1a-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/V1a assays. With the exception of peptides 5 and 6, all exhibit potent anti-V1a antagonism, with anti-V1a pA2 values in the range 7.64-8.33.(ABSTRACT TRUNCATED AT 400 WORDS)
Manning
M
M
Department of Biochemistry and Molecular Biology, Medical College of Ohio, Toledo 43699-0008.
Przybylski
J
J
Grzonka
Z
Z
Nawrocka
E
E
Lammek
B
B
Misicka
A
A
Cheng
L L
LL
Chan
W Y
WY
Wo
N C
NC
Sawyer
W H
WH
D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001127:Arginine Vasopressin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004231:Diuresis / Q000187:drug effects; D005029:Ethylenediamines / Q000737:chemistry*; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis; D051381:Rats
D000596:Amino Acids; D065092:Antidiuretic Hormone Receptor Antagonists; D005029:Ethylenediamines; D010455:Peptides; D001127:Arginine Vasopressin; C031234:ethylenediamine; C028884:1-(beta-mercapto-beta,beta-cyclopentamethylenepropionic acid)-2-(O-ethyl-Tyr)-4-Val-arginine vasopressin