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)
Pinski
J
J
Endocrine, Polypeptide and Cancer Institute, VA Medical Center, New Orleans, Louisiana, USA.
Schally
A V
AV
Yano
T
T
Groot
K
K
Srkalovic
G
G
Serfozo
P
P
Reissmann
T
T
Bernd
M
M
Deger
W
W
Kutscher
B
B
D000707:Anaphylaxis / Q000139:chemically induced; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D002918:Chymotrypsin / Q000737:chemistry / Q000378:metabolism; D002956:Citrulline / Q000031:analogs & derivatives / Q000737:chemistry*; D004487:Edema / Q000139:chemically induced; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006062:Gonadotropins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006727:Hormone Antagonists / Q000494:pharmacology*; D007986:Luteinizing Hormone / Q000097:blood / Q000187:drug effects; D008297:Male; D010060:Ovulation / Q000187:drug effects; D011402:Pronase / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011979:Receptors, Pituitary Hormone / Q000378:metabolism; D013329:Structure-Activity Relationship; D013381:Subtilisins / Q000737:chemistry / Q000378:metabolism
D006062:Gonadotropins; D006727:Hormone Antagonists; D011979:Receptors, Pituitary Hormone; D002956:Citrulline; D007987:Gonadotropin-Releasing Hormone; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D013381:Subtilisins; D002918:Chymotrypsin; D011402:Pronase; C062876:cetrorelix