Improved Brain Uptake and Pharmacological Activity Profile of Morphine-6-Glucuronide Using a Peptide Vector-Mediated Strategy

  1. Jamal Temsamani,
  2. Cécile Bonnafous,
  3. Christophe Rousselle1,
  4. Yannik Fraisse,
  5. Philippe Clair,
  6. Luc-André Granier,
  7. Anthony R. Rees2,
  8. Michel Kaczorek and
  9. Jean-Michel Scherrmann
  1. Synt:em, Parc Scientifique Georges Besse, Nîmes, France (J.T., C.B., Y.F., P.C., L.-A.G., A.R.R., M.K.); and Institut National de la Santé et de la Recherche Médicale U26, Hôpital Fernand Widal, Paris, France (C.R., J.M.S.)
  1. Address correspondence to:
    Dr. Jamal Temsamani, Synt:em, Parc Scientifique Georges Besse, 30000 Nîmes, France. E-mail: jtemsamani{at}syntem.com

Abstract

Morphine-6-glucuronide (M6G), an active metabolite of morphine, has been shown to have significantly attenuated brain penetration relative to that of morphine. Recently, we have demonstrated that conjugation of various drugs to peptide vectors significantly enhances their brain uptake. In this study, we have conjugated morphine-6-glucuronide to a peptide vector SynB3 to enhance its brain uptake and its analgesic potency after systemic administration. We show by in situ brain perfusion that vectorization of M6G (Syn1001) markedly enhances the brain uptake of M6G. This enhancement results in a significant improvement in the pharmacological activity of M6G in several models of nociception. Syn1001 was about 4 times more potent than free M6G (ED50 of 1.87 versus 8.74 μmol/kg). Syn1001 showed also a prolonged duration of action compared with free M6G (300 and 120 min, respectively). Furthermore, the conjugation of M6G results in a lowered respiratory depression, as measured in a rat model. Taken together, these data strongly support the utility of peptide-mediated strategies for improving the efficacy of drugs such as M6G for the treatment of pain.

Footnotes

  • Part of this work was carried out at Synt:em, Institut de Génétique Moléculaire of Montpellier.

  • doi:10.1124/jpet.104.081000.

  • ABBREVIATIONS: M6G, morphine-6-glucuronide; BBB, blood-brain barrier; TFA, trifluoroacetic acid; HPLC, high-pressure liquid chromatography; MALDI-TOF, matrix-assisted laser desorption-ionization time-of-flight mass spectrometry; DMF, dimethylformamide; DIEA, N, N,diisopropyletylamine; U-69593, (+)-(5α,7α,8β)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]benzeneacetamide; % MPE, percent maximum possible effect; ANOVA, analysis of variance.

  • ↵1 Current address: Agence Française de Sécurité Sanitaire des Produits de Santé, Saint Denis Cedex, France.

  • ↵2 Current address: MIP Technologies AB, Lund, Sweden.

    • Received November 17, 2004.
    • Accepted January 10, 2005.
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  1. doi: 10.1124/jpet.104.081000 JPET May 2005 vol. 313 no. 2 712-719
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