LH-RH antagonists: further analogs with ring-substituted aromatic residues

Although the systematic substitution of benzene and other aromatic ring systems with various atoms and groups has been a standard approach in conventional pharmaceutical research, it has only recently received the attention it deserves in peptide research. The observation that D-p-Cl-Phe inserted in position 2 of certain LH-RH (luteinizing hormone-releasing hormone) analogs results in large improvements in antagonist activity led us to examine the effect of this and other substituents on position 1 and 2 D-phenylalanyl analog side chains. Analogs containing two D-p-Cl-phenylalanines were found to be particularly powerful competitive inhibitors when assayed in cycling rat for blockade of ovulation. Analogs with non-aromatic amino acids in the first position exhibited much lower activities.