COMPARISON OF THE ANTIGONADOTROPIC ACTIVITY OF 3 GNRH ANTAGONISTS (NAL-GLU, ANTIDE AND CETRORELIX) IN A NONHUMAN PRIMATE MODEL (MACACA-FASCICULARIS)

We compared the antigonadotropic activity of the GnRH antagonists Nal- Glu, Antide and Cetrorelix in a non-human primate model (Macaca fascic ularis). Orchidectomized animals received a single subcutaneous inject ion at doses of 250 mug kg-1 (n = 4), 625 mug kg-1 (n = 4) and 1250 mu g kg-1 (n = 3) of the compounds Nal-Glu ([Ac-D-Nal(2)1, D-4-Cl-Phe2, D -Pal3, Arg5, D-Glu(AA)6, D-Ala10]-GnRH), Antide (Nal-Lys5, [Ac-D-Nal1, D-4-Cl-Phe2, D-Pal3, Nic-Lys5, D-Nic-Lys6, Ip-Lys8, D-Ala10]-GnRH) or Cetrorelix ([Ac-D-Nal1, D-4-Cl-Phe2, D-Pal3, D-Cit6, D-Ala10]-GnRH). Blood samples were collected before and 3, 6, 12, 24, 48, 72, and 96 h after GnRH antagonist administration. Serum was analysed for concentr ations of bioactive LH and immunoactive LH and FSH. All three compound s decreased LH secretion within 3-12 h (P < 0.05) and FSH secretion wi thin 12-48 h (P < 0.05) after injection. Major differences between the GnRH antagonists were observed with regard to the effective dose and duration of action. At a dose of 250 mug kg-1 Nal-Glu and Antide only transiently suppressed LH and FSH release, whereas Cetrorelix induced complete inhibition (P < 0.05) which lasted for the entire observation period. At a dose of 625 mug kg-1 Cetrorelix exhibited the longest du ration of action and Nal-Glu the shortest. At the highest dose of 1250 mug kg-1 Nal-Glu, Antide and Cetrorelix markedly inhibited LH and FSH secretion throughout the entire study period. With Nal-Glu (625 and 1 250 mug kg-1) bioactive LH secretion appeared more reduced compared to immunoactive LH. In conclusion, Nal-Glu, Antide and Cetrorelix are po tent inhibitors of LH and FSH secretion. In terms of the effective dos e and duration of action Cetrorelix appeared most active, followed by Antide and Nal-Glu in this experimental model. Thus, Antide and Cetror elix are highly interesting for clinical use.