Abstract
[N-Ac-Thr 1 ,D-Phe 2 ,D-Trp 3,6 ]-LHRH was the model antagonist of LHRH, which was the basis for tho design, synthesis and bioassay of seven peptides having four, five and six D-amino acids, which resulted from three single, three double, and one triple introductions of D-amino acids in positions 4, 5 and 8 of the model. Only the analog with six D-amino acids, [N-Ac-Thr 1 ,D-Phe 2 ,D-Trp 3 ,D-Ser 4, D-Tyr 5 ,D-Trp 6 ,D-Arg 8 ]-LHRH, had antiovulatory activity which was higher than that of the model antagonist, i.e., 70% antiovulatory activity at 25 μg/rat compared with 50% activity at 50 μg/rat, respectively. Empirical energy calculations gave a conformational structure for [N-Ac-Thr 1 ,D-Phe 2 ,D-Trp 3 , D-Ser 4 ,D-Tyr 5 ,D-Arg 6 ,D-Arg 8 ]-LHRH which is similar to that calculated for previous potent antagonists. These results are a basis of new designs of antagonists having D-sub-stituents in up to ten positions toward effective inhibitors of ovulation by the parenteral and oral routes of administration.