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-p-ClPhe2, 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 micrograms. Replacement of c-PzACAla in position 5 by O-phenyltyrosine significantly decreased potency.
Ljungqvist
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Institute for Biomedical Research, University of Texas, Austin.
Bowers
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Folkers
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D000595:Amino Acid Sequence; D000818:Animals; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000138:chemical synthesis / Q000494:pharmacology; D008969:Molecular Sequence Data; D010060:Ovulation / Q000187:drug effects; D051381:Rats
C081921:LHRH, N-Ac-3-(2-dibenzofuranyl)-Ala(1)-; C081920:LHRH, N-Ac-O-phenylTyr(1)-; D007987:Gonadotropin-Releasing Hormone