We report twelve analogues (1-12) of [Pmp1,D-Trp2,Arg8]oxytocin, PA (parent antagonist), (Pmp = beta,beta-pentamenthylene-beta-mercaptopropionic acid), which is a potent antagonist (pA2 = 7.77) of the uterotonic effect of oxytocin (OT) in rats. The analogues were designed by replacement of each optically active amino acid residue at positions 3-8 in PA with a D-amino acid. Analogues 1-8, featuring D-amino acids in the ring portion, were weaker antagonists than PA or were inactive. Unexpectedly, replacement with D-Cys6 gave analogue 9, pA2 = 8.29, which is more than 3 times as potent as PA, and replacement with D-Pen6 gave analogue 10, pA2 = 7.98, also more potent than PA. Replacement with D-Pro7 and D-Arg8 gave analogues 11 and 12, which are approximately equipotent or somewhat more potent than PA. These data suggest that neither the orientation of the tail sequence with respect to the plane of the ring portion of an antagonist nor the configuration of individual amino acids in the tail sequence may be critical for preservation of antagonism to the uterotonic action of OT. In the antidiuretic assay, analogues 9 and 12 were very weak partial agonists and had estimated pA2 = < 6.3 and < 5.6, respectively. Analogue 9 constitutes an interesting lead for the future design of OT antagonists with different molecular requirements than those featuring L-Cys6 as a substituent.