METABOLISM OF THE BROAD-SPECTRUM NEUROPEPTIDE GROWTH-FACTOR ANTAGONIST - [D-ARG(1), D-PHE(5), D-TRP(7,9), LEU(11)]-SUBSTANCE-P

Broad-spectrum neuropeptide, growth factor antagonists, such as [D-Arg (1), D-Phe(5), D-Trp(7,9), Leu(11)]substance P (antagonist D) and [Arg (6), D-Trp(7,9), NmePhe(8)]substance P((6-11)) (antagonist G), are cur rently being investigated as possible anti-tumour agents. These compou nds are hoped to be effective against neuropeptide-driven cancers such as small-cell lung cancer. Antagonist D possesses a broader antagonis tic spectrum than antagonist G and hence may be of greater therapeutic use. The in vitro metabolism of antagonist D has been characterised a nd the structures of two major metabolites have been elucidated by ami no acid analysis and mass spectrometry. Metabolism was confined to the C-terminus where serine carboxypeptidase action produced [deamidated] -antagonist D (metabolite 1) and [des-Leu(11)]-antagonist D (metabolit e 2) as the major metabolites. Biological characterisation of the meta bolites 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 determ ine which neuropeptides these compounds inhibit and on the relative po tency of that inhibition.