M. Manning et al., EFFECTS OF A D-CYS(6) L-CYS(6) INTERCHANGE IN NONSELECTIVE AND SELECTIVE VASOPRESSIN AND OXYTOCIN ANTAGONISTS/, Journal of medicinal chemistry, 38(10), 1995, pp. 1762-1769
We report the solid-phase synthesis of the D-Cys(6) analogues of argin
ine-vasopressin (AVP), peptide 1, of the selective AVP vasopressor (V-
1a, receptor) antagonist -(beta-mercapto-beta,beta-,pentamethyleneprop
ionic acid),2-O-methyltyrosine]arginine-vasopressin (d(CH2)(5)[Tyr(Me)
(2)]AVP, (A)), peptide 2, of the three nonselective antidiuretic/vasop
ressor (V-2/V-1a receptor) AVP antagonists d(CH2)(5)[Tyr(Et)(2)]VAVP (
B), d(CH2)(5)[D-Tyr(Et)(2)]VAVP (C), and d(CH2)(5)[D-Phe(2)]VAVP (D) (
where V = Val(4)), peptides 3-5, of the nonselective oxytocin (OT) ant
agonists d(CH2)(5)-[Tyr(Me)(2)]OVT (E) and d(CH2)(5)[Tyr(Me)(2),Thr(4)
,Tyr-NH29]OVT (F) (where OVT = ornithine-vasotocin), peptides 6 and 7,
and of the selective OT antagonists desGly-NH2,d(CH2)(5)[Tyr(Me)(2),T
hr(4)]OVT (G) and d(CH2)(5)[D-Trp(2),Thr(4)]OVT (H), peptides 8 and 9.
We also present the repeat syntheses of the previously reported d(CH2
)(5)[D-Trp(2)]AVT (peptide 10) and its D-Cys(6) analogue (peptide 11)
(where AVT = arginine-vasotocin). Peptides 1-11 were assayed for agoni
stic and antagonistic activities in in vivo V-1a V-2, and oxytocic ass
ays and in in vitro oxytocic assays without and with 0.5 mM Mg2+. With
V-2 and V-1a agonistic potencies of 0.82 and 0.41 units/mg, [D-Cys(6)
]AVP has retained less than 0.3% of the V-2 and V-1a, potencies of AVP
. It exhibits no oxytocic activity and is an in vitro OT antagonist. p
A(2) = 6.67 (no Mg2+); pA(2) = 5.24 (0.5 mM Mg2+). By contrast, with o
ne or two exceptions, a D-Cys(6)/L-Cys(6) interchange in antagonists 2
-9, although resulting in reductions of antagonistic potencies in all
assays for virtually all peptides 2-9 relative to A-H, has been well t
olerated. For peptides 2-5, the anti-V-2 and anti-V-1a, pA(2) values r
ange from similar to 5.54 to 7.33 and from 7.19 to 8.06, respectively;
the range of in vitro anti-OT pA(2) values (no Mg2+) is 7.35-7.87; wi
th 0.5 mM Mg2+, the range is 7.24-8.21. Peptides 2 and 4 have in vivo
anti-OT pA(2)s = 6.60 and 7.16, respectively. For peptides 6-9, the ra
nge of in vitro anti-OT pA(2) values (no Mg2+) is 7.65-7.96; with 0.5
mM Mg2+, the range is 7.41-7.65, and the in vivo anti-OT pA(2) values
range from 6.85 to 7.33. With an in vivo anti-OT pA(2) = 7.33, peptide
6 is equipotent with its parent E. The in vivo anti-OT potencies of p
eptides 7-9 are significantly reduced relative to those of F-H. The in
vitro anti-OT (0.5 mM Mg2+) pA(2) values of 10 and 11 are 7.54 and 7.
50, both significantly lower than those previously reported. Peptides
10 and 11 exhibit substantial V-1a antagonism. Their anti-V-1a, pA(2)
values are 7.56 and 7.53, respectively. The findings on peptides 2-9 s
how that a D-Cys(6)/L-Cys(6) interchange in cyclic AVP and OT antagoni
sts may be of limited value in enhancing antagonistic potency or selec
tivity. However, when combined with other appropriate molecular modifi
cations, this interchange may be of merit for the design of orally act
ive AVP and OT antagonists.