Design of potent and selective linear antagonists of vasopressor (V1-receptor) responses to vasopressin.
We report the solid-phase synthesis of 21 linear analogues of A and D, two nonselective antagonists of the vasopressor (V1) and antidiuretic (V2) responses to arginine vasopressin (AVP). A is Aaa-D-Tyr(Et)-Phe-Val-Asn-Abu-Pro-Arg-Arg-NH2 (where Aaa = adamantylacetyl at position 1). D is the des-Arg9 analogue of A. Nine new analogues of A (1-9) and 12 new analogues of D (10-21) were obtained. The following substitutions either alone or in combination were incorporated in A and/or in D: phenylacetic acid (Phaa) and tert-butylacetic acid (t-Baa) at position 1; D-Tyr2, D-Tyr(Me)2; Gln4; Arg6, Lys6, Orn6, MeAla7. The nine new analogues of A are (1) [Arg6], (2) [Lys6], (3) [Orn6], (4) [Phaa1,Lys6], (5) [Phaa1,Orn6], (6) [D-Tyr2], (7) [D-Tyr2,Arg6], (8) [Phaa1,D-Tyr2], (9) [Phaa1,D-Tyr2,Arg6]. The 12 new analogues of D are (10) [Arg6], (11) [Lys6], (12) [Orn6], (13) [Phaa1,Lys6], (14) [Phaa1,Gln4,Lys6], (15) [Phaa,D-Tyr(Me)2,Lys6], (16) [Phaa,D-Tyr(Me)2,Gln4,Lys6], (17) [Phaa1,D-Tyr2,Gln4,Lys6], (18) [t-Baa1,Lys6], (19) [t-Baa1,Gln4,Lys6], (20) [Arg6,MeAla7], (21) [t-Baa1,Arg6,MeAla7]. All 21 peptides were examined for agonistic and antagonistic potencies in AVP V2 and V1 assays in rats. With the exception of 6, the eight remaining new analogues of A are equipotent or more potent than A as V1 antagonists. Peptides 2-9 are less potent than A as V2 antagonists. Three, 4, 5, and 9, exhibit significant gains in anti-V1/anti-V2 selectivities (selectivity ratio = 41, 14, and infinite, respectively), compared to A (anti-V1, pA2 = 7.75 +/- 0.07; selectivity ratio = 0.44). Peptide 9 is unique in both series. It is a highly potent V1 antagonist (anti-V1 pA2 = 8.62 +/- 0.11 and is the first linear peptide to exhibit substantial antidiuretic agonism (4.1 +/- 0.2 units/mg). With the exception of 12, the remaining 11 analogues of D are 8-40 times more potent than D as V1 antagonists. Eight of these peptides exhibit significant gains in anti-V1/anti-V2 selectivities compared to D (anti-V1 pA2 = 7.43 +/- 0.06; selectivity ratio = 1.6).(ABSTRACT TRUNCATED AT 400 WORDS)
Manning
M
M
Department of Biochemistry, Medical College of Ohio, Toledo 43699-0008.
Stoev
S
S
Kolodziejczyk
A
A
Klis
W A
WA
Kruszynski
M
M
Misicka
A
A
Olma
A
A
Wo
N C
NC
Sawyer
W H
WH
D000595:Amino Acid Sequence; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001127:Arginine Vasopressin / Q000494:pharmacology*; D001681:Biological Assay; D001794:Blood Pressure / Q000187:drug effects; D004231:Diuresis / Q000187:drug effects; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011945:Receptors, Angiotensin / Q000187:drug effects; D017483:Receptors, Vasopressin; D013329:Structure-Activity Relationship
D057911:Angiotensin Receptor Antagonists; D009842:Oligopeptides; D011945:Receptors, Angiotensin; D017483:Receptors, Vasopressin; D001127:Arginine Vasopressin