Structure determination, pharmacological evaluation, and structure-activity studies of a new cyclic peptide substance P antagonist containing the new amino acid 3-prenyl-beta-hydroxytyrosine, isolated from Aspergillus flavipes

Two novel cyclic heptapeptides, peptides 1a and 1c, were isolated from an Aspergillus flavipes culture, originally isolated from soil, and their structures established by chemical and spectroscopic evidence. Peptide 1a contains a new amino acid, 3-prenyl-beta-hydroxytyrosine, and is a competitive antagonist to substance P at the human NK1 receptor, with an inhibitor affinity constant (Ki) of 8 +/- 4 microM. Methylation of 1a gave the monomethyl derivative 1b, which is a more potent competitive antagonist, with a Ki of 0.12 +/- 0.03 microM at the human NK1 receptor. Herein we report the structure determinations of 1a and 1c, and some structure-activity results. Several analogs of 1a were prepared by derivatization and synthesis. Structure-activity results for these analogs confirmed that the 3-prenyl-beta-hydroxytyrosine moiety is critical for the biological potency of 1a and 1b.