114056-26-7Relevant articles and documents
Effects of a D-Cys6/L-Cys6 interchange in nonselective and selective vasopressin and oxytocin antagonists
Manning,Ling Ling Cheng,Klis,Balaspiri,Olma,Sawyer,Nga Ching Wo,Chan
, p. 1762 - 1769 (2007/10/03)
We report the solid-phase synthesis of the D-Cys6 analogues of arginine- vasopressin (AVP), peptide 1, of the selective AVP vasopressor (V(1a) receptor) antagonist [1-(β-mercapto-β,β-pentamethylenepropionic acid),2- O-methyltyrosine]arginine-vasopressin (d(CH2)5[Tyr(Me)2]-AVP, (A)), peptide 2, of the three nonselective antidiuretic/vasopressor (V2/V(1a) receptor) AVP antagonism d(CH2)5[Tyr(Et)2]VAVP (B), d(CH2)5[D- Tyr(Et)2]VAVP (C), and d(CH2)5[D-Phe2]VAVP (D) (where V = Val4), peptides 3-5, of the nonselective oxytocin (OT) antagonists d(CH2)5[Tyr(Me)2]OVT (E) and d(CH2)5[Tyr(Me)2,Thr4,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,Thr4]OVT (G) and d(CH2)5[D- Trp2,Thr4]OVT (H), peptides 8 and 9. We also present the repeat syntheses of the previously reported d(CH2)5[D-Trp2]AVT (peptide 10) and its D- Cys6 analogue (peptide 11) (where AVT = arginine-vasotocin). Peptides 1-11 were assayed for agonistic and antagonistic activities in in vivo V(1a), V2, and oxytocic assays and in in vitro oxytocic assays without and with 0.5 mM Mg2+. With V2 and V(1a) agonistic potencies of 0.82 and 0.41 units/mg, [D- Cys6]AVP has retained less than 0.3% of the V2 and V(1a) potencies of AVP. It exhibits no oxytocic activity and is an in vitro OT antagonist. pA2 = 6.67 (no Mg2+); pA2 = 5.24 (0.5 mM Mg2+). By contrast, with one or two exceptions, a D-Cys6/L-Cys6 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 tolerated. For peptides 2-5, the anti-V2 and anti-V(1a) pA2 values range from ~5.54 to 7.33 and from 7.19 to 8.06, respectively; the range of in vitro anti-OT pA2 values (no Mg2+) is 7.35-7.87; with 0.5 mM Mg2+, the range is 7.24-8.21. Peptides 2 and 4 have in vivo anti-OT pA2s = 6.60 and 7.16, respectively. For peptides 6-9, the range of in vitro anti-OT pA2 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 pA2 values range from 6.85 to 7.33. With an in vivo anti-OT pA2 = 7.33, peptide 6 is equipotent with its parent E. The in vivo anti-OT potencies of peptides 7-9 are significantly reduced relative to those of F-H. The in vitro anti-OT (0.5 mM Mg2+) pA2 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) pA2 values are 7.56 and 7.53, respectively. The findings on peptides 2-9 show that a D-Cys6/L-Cys6 interchange in cyclic AVP and OT antagonists may be of limited value in enhancing antagonistic potency or selectivity. However, when combined with other appropriate molecular modifications, this interchange may be of merit for the design of orally active AVP and OT antagonists.
