NEW, HIGHLY-ACTIVE ANTAGONISTS OF LHRH WITH ACYLATED LYSINE AND P-AMINOPHENYLALANINE IN POSITION-5 AND POSITION-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 te sted 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 b est physico-chemical and biological properties were found for the foll owing two analogs: Pal-Ser-PicLys-D(PicSar)Lys-Leu-ILys-Pro-DAlaNH(2) (named Sartide) and -DPal-Ser-Tyr-D(PicSar)Lys-Leu-ILys-Pro-DAlaNH(2). They are both soluble in water, inhibit ovulation completely at 0.5 m u g per rat, and have ED(50) values for histamine release of about 30 mu g.mL. (C) Munksgaard 1994.