Metabolism of the anticancer peptide H-Arg-D-Trp-NmePhe-D-Trp-Leu-Met-NH2.

H-Arg-D-Trp-NmePhe-D-Trp-Leu-Met-NH2 (Antagonist G) will be the first broad-spectrum neuropeptide antagonist to enter a phase I clinical trial. Its in vitro and in vivo metabolism has been extensively characterized. The major metabolites were identified and their structures elucidated by mass spectroscopy and amino acid analysis. Metabolism occurred almost exclusively at the C-terminus and was arrested by phenylmethylsulfonylfluoride, a known serine-protease inhibitor. Biological characterization of the metabolites demonstrated that the degradation of Antagonist G produces metabolites that retain neuropeptide antagonist properties.