New, highly active antagonists of LHRH with acylated lysine and p-aminophenylalanine in positions 5 and 6.
A series of antagonists of the luteinizing hormone releasing hormone (LHRH) with substitutions in position 5 and/or 6 that included acylated lysine or p-aminophenylalanine were synthesized, characterized and tested for antiovulatory activity (AOA) in rats, and histamine releasing activity. Some of these antagonists were considerably more soluble at neutral pH than antagonists like Antide. Of 37 new antagonists, the best physico-chemical and biological properties were found for the following two analogs: NAcDNal-DCpa-DPal-Ser-PicLys-D(PicSar)Lys- Leu-ILys-Pro-DAlaNH2 (named Sartide) and NAcDNal-DCpa-DPal-Ser-Tyr-D(PicSar)Lys-Leu-IL ys-Pro-DAlaNH2. They are both soluble in water, inhibit ovulation completely at 0.5 microgram per rat, and have ED50 values for histamine release of about 30 micrograms/mL.
Institute for Biomedical Research, University of Texas at Austin.
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Janecka
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Janecki
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Bowers
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Folkers
D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D006632:Histamine / Q000096:biosynthesis; D006727:Hormone Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D008239:Lysine / Q000737:chemistry; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism; D008969:Molecular Sequence Data; D010060:Ovulation / Q000187:drug effects; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000737:chemistry; D051381:Rats
D006727:Hormone Antagonists; C009722:4-aminophenylalanine; D007987:Gonadotropin-Releasing Hormone; D010649:Phenylalanine; D006632:Histamine; D008239:Lysine