Synthesis and bioassay of LHRH-antagonists with N-Ac-d-O-phenyltyrosine and N-Ac-d-3-(2-dibenzofuranyl)alanine in position 1

N-Ac-d -O-phenyltyrosine was synthesized via the corresponding azlactone. Resolution of the dl methyl esters was achieved by Subtilisin Carlsberg. Treatment with palladium(II) acetate in trifluoroacetic acid converted N-Ac-d -O-phenyltyrosine into N-Ac-d -3-(2-dibenzofuranyl)alanine. These two amino acids were incorporated instead of N-Ac-d -2-Nal into position 1 of the LHRH-antagonist (N-Ac-d -2-Nal¹, d -pClPhe², d -3-Pal³, c-PzACAla⁵, d -PiCLyS⁶, ILys⁸,d -Ala¹⁰)-LHRH. The more rigid N-Ac-d -3-(2-dibenzofuranyl)alanine was structurally more effective than N-Ac-d -O-phenyltyrosine; the AOAs for the corresponding analogs were 82 and 38%, respectively, at 0.5 μg. Replacement of c-PzACAla in position 5 by O-phenyltyrosine significantly decreased potency.