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Chemical Compound Review

Antagonist G     (2S)-N-[(1S)-1-aminocarbonyl- 3...

Synonyms: AC1L4TXI, AR-1K5310, LS-172280, AC1Q5IQ7, C49H66N12O6S, ...
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Disease relevance of Antagonist G


High impact information on Antagonist G

  • [Arg(6), D-Trp(7,9), N(me)Phe(8)]-substance P (6-11) (antagonist G) induces AP-1 transcription and sensitizes cells to chemotherapy [3].
  • As well as acting as a neuropeptide receptor antagonist, antagonist G stimulates c-jun-N-terminal kinase (JNK) activity and apoptosis in SCLC cells [3].
  • This study shows that antagonist G stimulates apoptosis as assessed by morphology (EC50 = 5.9 +/- 0.1 and 15.2 +/- 2.7 microM for the H69 and H510 cell lines respectively) and stimulates c-jun-N-terminal kinase (JNK) activity in SCLC cells (EC50 = 3.2 +/- 0.1 and 15.2 +/- 2.7 microM) [4].
  • In view of these results we show that, as well as acting as a 'broad-spectrum' neuropeptide antagonist, antagonist G stimulates basal G-protein activity in SCLC cell membranes (81 +/- 12% stimulation at 10 microM), thereby displaying a unique ability to stimulate certain signal transduction pathways by activating G-proteins [4].
  • Marked accumulation of antagonist G (and its metabolites) was noted in the liver (AUC5278 micrograms/g x min) and to a lesser extent the spleen (AUC 930 micrograms/g x min) but only low levels appeared to cross the blood brain barrier (AUC in brain, 20 micrograms/g x min) or be taken up into the heart (AUC 101 micrograms/g x min) [5].

Chemical compound and disease context of Antagonist G


Biological context of Antagonist G


Anatomical context of Antagonist G


Associations of Antagonist G with other chemical compounds

  • METHODS: The hexapeptide antagonist G was covalently coupled via a thioether bond to the terminus of polyethylene glycol (PEG) in micelles formed from maleimide-derivatized poly(ethylene glycol) (Mr 2000) distearoylphosphatidylethanolamine followed by transfer into preformed liposomes during a one-step incubation [9].

Gene context of Antagonist G

  • RESULTS: The postinsertion approach to the formation of peptide-targeted liposomes led to the production of PLG bearing a maximum of approximately 0.3 microg antagonist G/micromol phospholipid [9].
  • A sensitive, high efficiency high-performance liquid chromatography (HPLC) method is described for the determination in human plasma of antagonist G and its three major metabolites, deamidated-G (M1), G-minus Met11 (M2) and G[Met11(O)] (M3) [10].
  • Our results showed that radiolabeled antagonist G-targeted sterically stabilized liposomes (SLG) bound to H69 cells with higher avidity than free antagonist G and were internalized (reaching a maximum of 13000 SLG/cell), mainly through a receptor-mediated process, likely involving clathrin-coated pits [6].

Analytical, diagnostic and therapeutic context of Antagonist G

  • In stage 2, dose intensity was increased to weekly, and the inhibitory effect of i.v. Antagonist G was assessed by forearm blood flow (FBF) using SP as a vasodilator, as measured by venous plethysmography [1].
  • [Arg6, D-Trp7.9, NmePhe8]-substance P (6-11) (antagonist G) is a broad spectrum neuropeptide growth factor antagonist about to enter clinical trials as an anticancer drug [11].
  • Differential scanning calorimetry studies were conducted to determine the freeze-drying cycle parameters which resulted in a stable, lyophilized formulation of Antagonist G [12].
  • Degradation of the basic peptide [Arg6,D-Trp7,9,MePhe8]-substance P (6-11) (antagonist G) was monitored with reversed-phase high-performance liquid chromatography, free capillary zone electrophoresis, and capillary zone electrophoresis with a capillary cationic coating [13].
  • Rate constants of the alkaline degradation of antagonist G measured with reversed-phase high-performance liquid chromatography and capillary zone electrophoresis with a dynamic coated capillary wall are similar whereas the values measured with free zone capillary electrophoresis are lower [13].


  1. Forearm blood flow and local responses to peptide vasodilators: a novel pharmacodynamic measure in the phase I trial of antagonist G, a neuropeptide growth factor antagonist. Clive, S., Webb, D.J., MacLellan, A., Young, A., Byrne, B., Robson, L., Smyth, J.F., Jodrell, D.I. Clin. Cancer Res. (2001) [Pubmed]
  2. Characterization of the deamidase enzyme responsible for the metabolism of the anticancer peptide: H-Arg-D-Trp-NmePhe-D-Trp-Leu-Met-NH2. Jones, D.A., Cummings, J., Langdon, S.P., MacLellan, A., Smyth, J.F. Biochem. Pharmacol. (1995) [Pubmed]
  3. [Arg(6), D-Trp(7,9), N(me)Phe(8)]-substance P (6-11) (antagonist G) induces AP-1 transcription and sensitizes cells to chemotherapy. MacKinnon, A.C., Waters, C., Rahman, I., Harani, N., Rintoul, R., Haslett, C., Sethi, T. Br. J. Cancer (2000) [Pubmed]
  4. [Arg6,D-Trp7,9,NmePhe8]-substance P (6-11) activates JNK and induces apoptosis in small cell lung cancer cells via an oxidant-dependent mechanism. MacKinnon, A.C., Armstrong, R.A., Waters, C.M., Cummings, J., Smyth, J.F., Haslett, C., Sethi, T. Br. J. Cancer (1999) [Pubmed]
  5. Pharmacokinetics, metabolism, tissue and tumour distribution of the neuropeptide growth factor antagonist [Arg6, D-Trp7,9, NmePhe8]- substance P(6-11) in nude mice bearing the H69 small-cell lung cancer xenograft. Cummings, J., MacLellan, A.J., Jones, D.A., Langdon, S.P., Rozengurt, E., Ritchie, A.A., Smyth, J.F. Ann. Oncol. (1995) [Pubmed]
  6. A growth factor antagonist as a targeting agent for sterically stabilized liposomes in human small cell lung cancer. Moreira, J.N., Hansen, C.B., Gaspar, R., Allen, T.M. Biochim. Biophys. Acta (2001) [Pubmed]
  7. Stability and in vitro metabolism of the mitogenic neuropeptide antagonists [D-Arg1,D-Phe5, D-Trp7,9, Leu11]-substance P and [Arg6, D-Trp7,9, MePhe8]-substance P (6-11) characterized by high-performance liquid chromatography. Cummings, J., MacLellan, A., Langdon, S.P., Smyth, J.F. Journal of pharmaceutical and biomedical analysis. (1994) [Pubmed]
  8. Preclinical studies on the broad-spectrum neuropeptide growth factor antagonist G. Jones, D.A., Cummings, J., Langdon, S.P., Smyth, J.F. Gen. Pharmacol. (1997) [Pubmed]
  9. Use of the post-insertion technique to insert peptide ligands into pre-formed stealth liposomes with retention of binding activity and cytotoxicity. Moreira, J.N., Ishida, T., Gaspar, R., Allen, T.M. Pharm. Res. (2002) [Pubmed]
  10. Development of a gradient elution high-performance liquid chromatography assay with ultraviolet detection for the determination in plasma of the anticancer peptide [Arg6, D-Trp7,9, mePhe8]-substance P (6-11) (antagonist G), its major metabolites and a C-terminal pyrene-labelled conjugate. Cummings, J., MacLellan, A.J., Mark, M., Jodrell, D.I. J. Chromatogr. B Biomed. Sci. Appl. (1999) [Pubmed]
  11. Processing of the neuropeptide growth factor antagonist [Arg6, D-Trp7.9, NmePhe8]-substance P (6-11) by a small cell lung cancer cell line (H69). Cummings, J., MacLellan, A.J., Langdon, S.P., Jones, D.A., Rozengurt, E., Smyth, J.F. Biochem. Pharmacol. (1995) [Pubmed]
  12. Pharmaceutical development of a parenteral lyophilized formulation of the investigational antitumor neuropeptide antagonist [Arg6, D-Trp7,9, MePhe8]-Substance P [6-11]. Jonkman-de Vries, J.D., Rosing, H., Talsma, H., Henrar, R.E., Kettenes-van den Bosch, J.J., Bult, A., Beijnen, J.H. Investigational new drugs. (1998) [Pubmed]
  13. Reversed-phase high-performance liquid chromatography and capillary electrophoresis in the stability study of the neuropeptide growth factor antagonist [Arg6,D-Trp7,9,MePhe8]-substance P (6-11): a comparative study. Reubsaet, J.L., Beijnen, J.H., Bult, A., Teeuwsen, J., Koster, E.H., Waterval, J.C., Underberg, W.J. Anal. Biochem. (1994) [Pubmed]
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