Improvement in Potency of an Oxytocin Antagonist after Systematic Substitutions with L-Tryptophan

George Flouret, William Brieher, Kevin Mahan, Tadeusz Majewski, Laird Wilson

Research output: Contribution to journalArticlepeer-review


We report twelve analogues (1-12) of [Pmp1,D-Trp2,Arg8]oxytocin, ANTAG (Pmp = β,β-pentamethylene-β- mercaptopropionic acid), which is a potent antagonist (pA2 = 7.77) of the uterotonic effect of oxytocin (OT) in rats, as measured in a uterotonic assay. Nine of the following analogues were designed by replacement of each of the nine residues in ANTAG with an L-tryptophan residue: [Ac-Trp1,D-Trp2,Val6,Arg8]OT (1), [Pmp1,Trp2,Arg8]OT (2), [Pmp1, D-Trp2,Trp3,Arg8]OT (3), [Pmp1,D-Trp2,Trp4,Arg8]OT (4), [Pmp1,D-Trp2,Trp6,Arg8]OT (5), [Pmp2,Trp6,Arg8]OT (6), [Aaa1,D-Trp2,Val6,Arg8]OT (7), [Pmp1,D-Trp2,Ica7,Arg8]OT (8), [Pmp1,D-Trp2,Trp7Arg8]OT (9), [Pmp1,D-Trp2,Trp8]OT (10), [Pmp1,D-Trp2,Arg8,Trp9]OT (11), [Pmp1,D-Trp2,Arg8,Trp(For)9]OT (12). In these analogues Aaa = 1-adamantaneacetic acid, and Ica = indoline-2-carboxylic acid. All linear analogues and analogues featuring Trp substitutions in the ring sequence of ANTAG were OT antagonists of lower potency than the parent peptide. All the analogues featuring Trp subtitutions in the tail sequence of ANTAG were OT antagonists of equal or better potency than the parent peptide. Replacement with Iea7 gave analogue 8, equipotent with ANTAG, but replacement with Trp7 gave analogue 9, which shows almost a two-fold increase in potency (pA2 = 8.06). Replacement with Trp9 gave analogue 11 (pAs = 8.03) which is about 1.8 times more potent than the parent antagonist, although Trp(For)9 had lower potency. Of great interest is that substitution with Trp8 leads to a more potent analogue, 10 (pÁ2 = 8.22), which, unlike most antidiuretic hormone anatagonists, lacks any cationic charge in the molecule. The antidiuretic assay shows antagonists 9-11 to be weak antagonists of [Arg8]vasopressin, the antidiuretic hormone, with pA2 ≤ 6.0; hence, they may be interesting leads for future design of more potent and specific OT antagonists.

Original languageEnglish (US)
Pages (from-to)2089-2094
Number of pages6
JournalJournal of Medicinal Chemistry
Issue number7
StatePublished - Jul 1 1991
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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