Design of Potent Oxytocin Antagonists Featuring D-Tryptophan at Position 2

George Flouret, William Brieher, Kevin Mahan, Laird Wilson

Research output: Contribution to journalArticlepeer-review


We prepared nine analogues (1-9) of MCPA-D-Phe-Phe-Ile-Asn-Cys-Pro-Arg-Gly-NH2, [MCPA1, D-Phe2, Phe3, Iie4, Arg8]oxytocin (MCPA = β-mercapto-β,β-pentamethylenepropionic acid), a potent antagonist of the rat uterotonic action of oxytocin (OT). We replaced D-Phe with D-Trp and made [MCPA1,D-Trp2,Phe3, Iie4,Arg8]OT (1), which had OT pA2 of 7.51, somewhat higher than that of the D-Phe2 antagonist which has OT pA2 = 7.35 in our rat uterotonic assay. Both compounds are equipotent as antagonists of [Arg8] vasopressin in the rat antidiuretic assay, with pA2= 8.1. Other substitutions gave [MCPA1,D-Trp2,4-Cl-Phe3, Iie4,Arg8]OT (2), OT pA2 7.44; [MCPA1d- Trp2,Phe3, Ile4,3,4-dehydro-Pro7,Arg8]OT (3), OT pA2 = 7.42; [MCPA1, D-Trp2,Phe3,Arg8]OT (4), OT pA2 = 7.58; [MCPA1,D-Trp2,Phe3,Arg8,Gly9-NHEt]OT (5), OT pA2 = 7.49; [MCPA1,D-Trp2, Iie4,Arg8]OT (6), OT pA2 = 7.46; [MCPA1,D-Trp2,Val4,Arg8]OT (7), OT pA2 = 7.58; [MCPA1,D-Trp2,Thr4,Arg8]OT (8), OT pA2 = 7.48; and finally, [MCPA1,D-Trp2,Arg8]OT (9), which was a more potent and more selective OT antagonist, with OT pA2 = 7.77 in the uterotonic assay and ADH pA2 < 5.9 in the antidiuretic assay and hence is an important lead for the design of OT antagonists.

Original languageEnglish (US)
Pages (from-to)642-646
Number of pages5
JournalJournal of Medicinal Chemistry
Issue number2
StatePublished - Feb 1 1991
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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