Highly potent antagonists of luteinizing hormone-releasing hormone free of edematogenic effects

S. Bajusz, M. Kovacs, M. Gazdag, L. Bokser, T. Karashima, V. J. Csernus, T. Janaky, J. Guoth, A. V. Schally

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Abstract

To eliminate the undesirable edematogenic effect of the luteinizing hormone-releasing hormone (LH-RH) antagonists containing basic D amino acids at position 6, exemplified by [Ac-D-Phe(pCl)1,2,D-Trp3,D-Arg6,D-Ala10]LH-RH [Phe(pCl) indicates 4-chlorophenylalanine], analogs with D-ureidoalkyl amino acids such as D-citrulline (D-Cit) or D-homocitrulline (D-Hci) at position 6 were synthesized and tested in several systems in vitro and in vivo. HPLC analysis revealed that the overall hydrophobicity of the D-Cit/D-Hci6 analogs was similar to that of the basic D-Arg6 antagonists. In vitro, most of the analogs completely inhibited LH-RH-mediated luteinizing hormone release in perfused rat pituitary cell systems at an antagonist to LH-RH molar ratio of 5:1. In vivo, the most active peptides, [Ac-D-Nal(2)1,D-Phe(pCl)2,D-Trp3,D-Cit6,D-Ala10]LH-RH[Nal(2) indicates 3-(2-naphthyl)alanine] and its D-Hci6 analog, caused 100% inhibition of ovulation in cycling rats in doses of 3 μg and suppressed the luteinizing hormone level in ovariectomized female rats for 47 hr when administered at doses of 25 μg. Characteristically, these peptides did not exert any edematogenic effects even at 1.5 mg/kg. These properties of the D-Cit/D-Hci6 antagonists may make them useful clinically.

Original languageEnglish (US)
Pages (from-to)1637-1641
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume85
Issue number5
DOIs
StatePublished - Jan 1 1988
Externally publishedYes

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