Metabolism of the broad-spectrum neuropeptide growth factor antagonist: [D-Arg1, D-Phe5, D-Trp7,9, Leu11]-substance P.
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.
Jones
D A
DA
Medical Oncology Unit, Western General Hospital, Edinburg, UK.
Cummings
J
J
Langdon
S P
SP
Maclellan
A J
AJ
Higgins
T
T
Rozengurt
E
E
Smyth
J F
JF
D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D001839:Bombesin / Q000037:antagonists & inhibitors; D004355:Drug Stability; D008099:Liver / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000378:metabolism; D010664:Phenylmethylsulfonyl Fluoride / Q000494:pharmacology; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013329:Structure-Activity Relationship; D013373:Substance P / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism
D000970:Antineoplastic Agents; D010446:Peptide Fragments; C046958:substance P (6-11), Arg(6)-Trp(7,9)-Me-Phe(8)-; D013373:Substance P; D010664:Phenylmethylsulfonyl Fluoride; C045800:substance P, Phe(5)-Trp(7,9)-Leu(11)-; D001839:Bombesin