PMID: 8611370Mar 1, 1996Paper

Metabolism of the broad-spectrum neuropeptide growth factor antagonist: [D-Arg1, D-Phe5, D-Trp7,9, Leu11]-substance P

British Journal of Cancer
D A JonesJ F Smyth

Abstract

Broad-spectrum neuropeptide growth factor antagonists, such as [D-Arg1, D-Phe5, D-Trp7,9, Leu11]substance P (antagonist D) and [Arg6, D-Trp7,9, NmePhe8]substance P(6-11) (antagonist G), are currently being investigated as possible anti-tumour agents. These compounds are hoped to be effective against neuropeptide-driven cancers such as small-cell lung cancer. Antagonist D possesses a broader antagonistic spectrum than antagonist G and hence may be of greater therapeutic use. The in vitro metabolism of antagonist D has been characterised and the structures of two major metabolites have been elucidated by amino acid analysis and mass spectrometry. Metabolism was confined to the C-terminus where serine carboxypeptidase action produced [deamidated]-antagonist D (metabolite 1) and [des-Leu11]-antagonist D (metabolite 2) as the major metabolites. Biological characterisation of the metabolites demonstrated that these relatively minor changes in structure resulted in a loss of antagonist activity. These results provide some of the first structure-activity information on the factors that determine which neuropeptides these compounds inhibit and on the relative potency of that inhibition.

Citations

Apr 4, 2002·Proceedings of the National Academy of Sciences of the United States of America·Daniel ChanPaul Bunn
Sep 14, 2000·Neuropeptides·C MarquezT W Moody

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