EFFECTIVE ANTAGONISTS OF THE LUTEINIZING HORMONE RELEASING HORMONE WHICH RELEASE NEGLIGIBLE HISTAMINE

摘要

Antide is the decapeptide, N-Ac-D-2-Nal,D-pClPhe, D-3- Pal, Ser,NicLys, D-NicLys, Leu, ILys, Pro, D-Ala, NH2 which is an antagonist of luteinizing hormone releasing hormone (LHRH). This decapeptide, like others of the present invention, has high antiovulatory activity (AOA) and releases negligible histamine. Numerous other peptides having structures related to Antide were prepared and tested. These peptides had variations primarily in positions 5, 6, 7, and 8. Of these, N-Ac-D-2-Nal, D-pClPhe,D-3-Pal,Ser,PicLys,cis-DPzACAla,Leu,ILys,Pro,D-Ala-NH2 was one of the most potent and had higher antiovulatory activity than Antide, i.e. 73%/0.25ug and 100%/0.5ug vs. 36%/0.5ug and 100%/1.Oug. Antide showed significant, (p<0.001) duration of action, when injected at a dose of 10ug, 44 hours before 50 ng of the agonist, ¢D-3-Qal6!-LHRH. Antide showed oral AOA at 600ug (73%) and at 1200ug (100%) with negligible difference being found between water and corn oil oral formulations. In the antagonists prepared according to the present invention, arginine and its derivatives were not utilized. Lysine was converted into derivatives with acyl groups or with alkyl groups on the E-amino group. The amino acid ornithine was acylated or alkylated on the d-amino group. Both the L- and D- forms of lysine and the L-form of ornithine were used in synthesizing these acyl and alkyl derivatives. Structurally related intermediates were also synthesized. All together, many new peptides were synthesized by the basic and minimal concepts of ten variables for anti-ovulation activity and ten variables for histamine release, which may be independent or partially overlapping.