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Antiovulatory antagonists of LHRH related to antide
Author(s) -
Flouret George,
Arnold Zdzislaw S.,
Majewski Tadeusz,
Petousis Nikolaos H.,
Mahan Kevin,
Farooqui Firdous,
Blum Katherine A.,
Konopinska Danuta,
Natarajan Swaminathan,
Crich David
Publication year - 1995
Publication title -
journal of peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 66
eISSN - 1099-1387
pISSN - 1075-2617
DOI - 10.1002/psc.310010202
Subject(s) - microgram , chemistry , ed50 , antagonist , stereochemistry , chromatography , biochemistry , in vitro , receptor
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‐NH 2 , 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 Ilys 8 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), ED 50 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 ED 50 , 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, ED 50 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 ED 50 was 116 μg/ml; [ D ‐Lys (2‐Pyc) 6 ]Antide gave 3/8 at 1 μg, and in the HRA, ED 50 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 Lys 5 or D ‐Lys 6 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.