Peptide antagonists of LH-RH: large increases in antiovulatory activities produced by basic D-amino acids in the six...

It has been assumed, usually with good reason, that D-amino acids with large aromatic side-chains must be present in position 6 of both LH-RH superagonists and antagonists for the highest levels of biological activity to be reached. However, using one of a recent generation of potent lH-RH inhibitory analogs as a model, we have found that the insertion of D-lysine or, better still, D-arginine in this position results in greater antiovulatory activity in the rat over corresponding D-phenylalanine6- and D-tryptophan6-analogs. For instance, [Ac-D-p-Cl-Phe1,2,D-Trp3,D-Arg6,D-Ala10]-LH-RH exhibits antiovulatory activity at a dose of 750 ng per animal and appears to be the first competitive antagonist with activity in the nanogram region in vivo. This effect seems to be highly dependent on the degree of basicity of the amino acid side-chain since D-amino acids with neutral or acidic groups produced far less active compounds.