Synthesis and biological activity of LH-RH antagonists modified in position 1

As part of our studies on the design of more potent antagonists of the LH-RH (luteinizing hormone-releasing hormone) decapeptide, twelve new highly soluble D-Arg6-analogs have been synthesized. These peptides contain modifications in position 1 and are typified by the general formula (N-acetyl-X1, D-p-Cl-Phe2, D-Trp3, D-Arg6, D-Ala10) LH-RH. We have found that a lyophilic, aromatic substituent is required in position 1 in order to elicit antiovulatory activity at a dose as low as 3 micrograms. The larger the hydrophobic amino acid (X: p-Br-Phe, beta-Nal-2) in position 1, the higher is the antiovulatory activity that can be attained. Analogs with non-aromatic or hydrophilic amino acids (X: Gly, Leu, Arg, His, Glu) in position 1 generally have much lower activities in this series of LH-RH antagonists.