115499-13-3Relevant articles and documents
Solid-phase synthesis of 16 potent (selective and nonselective) in vivo antagonists of oxytocin
Manning,Kruszynski,Bankowski,Olma,Lammek,Cheng,Klis,Seto,Haldar,Sawyer
, p. 382 - 391 (2007/10/02)
We describe the synthesis and some pharmacological properties of 16 new in vivo antagonists of oxytocin. These are based on modifications of three peptides: A, B, and C. A is our previously reported potent and selective antagonist of the vasopresor (V1 receptor) responses to arginine-vasopressin (AVP)/weak oxytocin antagonist, [1-(β-mercapto-β,β-pentamethylenepropionic acid), 2-O-methyltyrosine]arginine-vasopressin (d(CH2)5[Tyr(Me)2]AVP. B reported here, the Ile3 analogue of A, is d(CH2)5[Tyr(Me)2]AVT (5 below) and C is our previously reported potent nonselective oxytocin antagonist/AVP V1 antagonist, [1-(β-mercapto-β,β-pentamethylenepropionic acid),2-O-methyltyrosine,8-ornithine]vasotocin (d(CH2)5[Tyr(Me)2]OVT). The following substitutions and deletions, alone or in combination, were employed in A, B, and C: 1-deaminopenicillamine (dP); D-Tyr(Alk)2 (where Alk = Me or Et), D-Phe2; Val4, Thr4; Δ3-Pro7; Lys8, Cit8, Orn8; desGly9, desGly-NH29, Ala-NH29; Leu-NH29; Arg-NH29. The 16 new analogues are (1) d(CH2)5[D-Tyr(ME)2]AVP, (2) d(CH2)5[D-Tyr(ME)2,Val4,Δ3-Pro7']AVP, (3) d(CH2)5[D-Tyr(Et)2,Val4,Lys8]VP, (4) d(CH2)5[D-Tyr(Et)2,Val4,Cit8]VP, (5) d(CH2)5[Tyr(Me)2]AVT, (6) d(CH2)5[Tyr(Me)2,Lys8]VT, (7) dP[Tyr(Me)2]AVT, (8) dP[Tyr(ME)2,Val4]AVT, (9) d(CH2)5[D-Tyr(Me)2,Val4]AVT, (10) d(CH2)5[D-Phe2,Val4]AVT, (11) d(CH2)5[Tyr(Me)2,Thr4]OVT, (12) d(CH2)5[Tyr(Me)2,Thr4,Ala-NH29]OVT, (13) d(CH2)5[Tyr(Me)2,Thr4,Leu-NH29]OVT, (14) d(CH2)5[Tyr(Me)2,Thr4,Arg-NH29]OVT, (15) desGly-NH29,d(CH2)5[Tyr(Me)2,Thr4]OVT, (16) desGly9,d(CH2)5[Tyr(Me)2,Thr4]OVT. 1-4 are analogues of A, 5-10 are analogues of B, and 11-16 are analogues of C. Their protected precursors were synthesized either entirely by the solid-phase method or by a combination of solid-phase and solution methods (1 + 8 or 8 + 1 couplings). All analogues were tested in rats for agonistic and antagonistic activities in oxytocic (in vitro, without and with Mg2+, and in vivo) assays as well as by antidiuretic and vasopressor assays. All analogues exhibit potent oxytocic antagonism in vitro and in vivo. With an in vitro pA2 (in the absence of Mg2+) = 9.12 ± 0.09, dP[Tyr(Me2]AVT (7) is one of the most potent in vitro oxytocin antagonists reported to date. Fifteen of these analogues (all but 6) appear as potent or more potent in vivo oxytocin antagonists than C (pA2 = 7.37 ± 0.17). Analogues 1-9 and 14 are potent AVP V1 antagonists. Their anti-V1 pA2 values range from 7.92 to 8.45. They are thus nonselective oxytocin antagonists. The remaining six analogues (10-13, 15, 16) exhibit substantially reduced anti-V1 potencies relative to their antioxytocic potencies in vivo and are thus far more selective as oxytocin antagonists than C. d(CH2)5[Tyr(Me)2,Thr4,Leu-NH29]OVT (13) and desGly-NH29,d(CH2)5[Tyr(Me)2,Thr4]OVT (15) are among the most selective in vivo oxytocin antagonists reported to date. These findings provide useful clues for the design of even more potent and selective in vivo oxytocin antagonists. Some of the analogues reported here may be of value for the treatment of premature labor and/or as pharmacological tools for studies on the physiological and pathophysiological roles of oxytocin and of AVP.
