Structure-activity studies of antagonists of luteinizing hormone-releasing hormone with emphasis on the amino-terminal region.
The structure-activity relationship of the hydrophobic amino terminal region of the antagonist [N-Ac-D-Nal1,D-pClPhe2,D-Trp3,D-Arg6,Phe7,D-Ala10]-LH- RH has been investigated by the incorporation of a variety of amino acids with emphasis on positions 1, 2, and 3. The analogues were prepared by routine solid-phase peptide synthesis. All purifications were performed in two stages: gel permeation chromatography followed by preparative, reversed-phase, high-performance chromatography. The analogues were assayed in a standard rat antiovulatory assay using a 40% propane-1,2-diol-saline vehicle. A simplified antagonist was developed that allowed the removal of the custom-synthesized D-pClPhe and the labile D-Trp while retaining antiovulatory potency. The compound [N-Ac-D-Nal1,D-Phe2,3,D-Arg6,Phe7,D-Ala10]-LH-RH caused a 56% blockade of ovulation at the 500-ng dose and is approximately equipotent with the parent analogue in this system.
D000595:Amino Acid Sequence; D000818:Animals; D004353:Drug Evaluation, Preclinical; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors; D010060:Ovulation / Q000187:drug effects*; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D007987:Gonadotropin-Releasing Hormone