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

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.