Evaluation of the in vitro and in vivo activity of the L-, D,L- and D-Cit6 forms of the LH-RH antagonist Cetrorelix (SB-75).

The objective of this study was to examine the in vivo and in vitro gonadotropin-inhibiting potencies, edematogenic activities and the receptor binding affinities of the D-Cit6, D,L-Cit6 and L-Cit6 forms of the LH-RH antagonist Cetrorelix (SB-75) [Ac-D-Nal(2)1,D-Phe(4Cl)2,D-Pal(3)3,D-Cit6,D-Ala10]LH- RH. In order to demonstrate the suppressive effects of two different diastereomers of SB-75 and their racemic mixture on LH and FSH release, [D-Cit6] SB-75 was injected subcutaneously in doses of 2.5 and 10 micrograms/rat, [D,L-Cit6]-SB-75 in doses of 5 and 20 micrograms/rat and [L-Cit6] SB-75 in doses of 12.5 and 50 micrograms/rat to castrated male rats. Two hours after administration, there was no difference in LH levels between rats injected with the L-form and control animals, indicating a low activity and/or a rapid enzymatic degradation of this peptide. The (1:1) diastereomeric mixture was only about half as potent in suppression of LH release compared to [D-Cit6] SB-75. Serum FSH levels were suppressed significantly (p < 0.01) for more than 48 h after the administration of 10 micrograms [D-Cit6] SB-75 and 20 micrograms of [D,L-Cit6] SB-75, respectively. [D-Cit6] SB-75 administered at a dose of 2 micrograms/rat induced 100% inhibition of ovulation, while 4 micrograms/rat of the D,L-Cit6 peptide were necessary to produce the same effect.(ABSTRACT TRUNCATED AT 250 WORDS)