Design, Synthesis and Biological Evaluation of Antagonists of LHRH by Criteria of Potency, Safety and Solubility

Some analogs of Antide and congeners with higher water solubility have been synthesized by substitutions in positions 1, 5 or 6 with hydrophilic residues. In position 1, D-3-Qal has been incorporated in four peptides and D-3-Pal in one peptide. In positions 5 and 6, D and L-3-Pal, PzAla and (DSer)Lys have been tried. In one peptide, D—(AcDSer)Lys was substituted in position 6.Most of the new analogs had lower AOA (antiovulatory activity) than the parent compounds but three potent analogs were identified. The first one, [N — Ac— D — 3-Qal1,DpClPhe2,D— 3-Pal3,c-PzACAla5,D — PicLys6,ILys8,D — Ala10]— LHRH, had 55% AOA at 0.25 μg and 100% at 0.5 μg. Its ED50 for in vitro histamine release was 171 ± 17 μg/ml which is an increase from 49±4.8 μg/ml for the parent compound with N—Ac-D-2-Nal [1].The second analog, [N — Ac— D — 2-Nal1,DpClPhe2,D — 3-Pal3,PicLys5,D — (DSer)Lys6,ILys8,D—Ala10] — LHRH, had 69% AOA at 0.25 μg and 95% at 0.5 μg. This analog released somewhat more histamine than the parent analog featuring D-PicLys6, the ED50 being 18 μg/ml compared to 93 ± 11 for the parent analog.The third analog is:[N — Ac— D— 2-Nal1,DpClPhe2,D— 3-Pal3,c-PzACAla5,D—PzAla6,ILys8,DAla1]— LHRH. The AOA for this analog was 63% at 0.25 μg and the ED50 for histamine release 88±6.4 μg/ml.