Antiovulatory antagonists of LHRH related to antide

We report 104 analogues of the potent antiovulatory antagonist of LHRH, N‐Ac‐D‐Nal‐D‐Cpa‐D‐Pal‐Ser‐Lys(Nic)‐D‐Lys(Nic)‐Leu‐Ilys‐Pro‐D‐Ala‐NH2, Antide. We replaced the Nic group in Antide with other acyl substituents to modulate size, hydrophilicity or basicity of the molecule, we also replaced th Lys residues with shorter basic amino acids, and made cyclic 5/6 analogues as well as position 5 or 6 dimers. We substituted Ilys8 with other alkyl groups and acyl derivatives. When injected in 0.1% DMSO in water in a typical antiovulatory (AO) assay, Antide gives six rats ovulating out of eight (6/8) at 2 μg, 4/8 at 4 μg, and the histamine release assay (HRA), ED50 is >300 μg/ml; [Lys(N‐Isobutyl)8]Antide gave 2/8 at 2 μg/rat; [Lys (8‐Qis)5]Antide gave 1/8 at 1 μg, and 0/8 at 2 μg, and in the HRA ED50, 22 μg/ml; [D‐Lys(8‐Qis)6]Antide gave 4/8 at 1 μg and 0/8 at 2 μg, and in the HRA, ED50 was 27 μg/ml; [Lys(8‐Qic)8] gave 5/8 at 1 μg, 1/8 at 2 μg/ [Lys(2‐Pyc)5]Antide gave 5/8 at 1 μg and 0/8 at 2 μg, and in the HRA ED50 was 116 μg/ml; [D‐Lys (2‐Pyc)6]Antide gave 3/8 at 1 μg, and in the HRA, ED50 was 100 ‐ >300 μg/ml; [Lys(2‐Pyc)5,D‐Lys(2‐Pyc)6]Antide gave 2/8 at 1 μg. The substitutions of the Nic groups of Antide at Lys5 or D‐Lys6 with 8‐Qis or with 2‐Pyc groups seem to give highly potent antiovulatory antagonists of LHRH and constitute significant new leads to generate potent antiovulatory compounds endowed with moderate or low histamine release.