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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on January 12, 2005; DOI: 10.1124/jpet.104.081000

0022-3565/05/3132-712-719$20.00
JPET 313:712-719, 2005
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NEUROPHARMACOLOGY

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

Jamal Temsamani, Cécile Bonnafous, Christophe Rousselle1, Yannik Fraisse, Philippe Clair, Luc-André Granier, Anthony R. Rees2, Michel Kaczorek, and Jean-Michel Scherrmann

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.)

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.

Received November 17, 2004; accepted January 10, 2005.

Address correspondence to: Dr. Jamal Temsamani, Synt:em, Parc Scientifique Georges Besse, 30000 Nîmes, France. E-mail: jtemsamani{at}syntem.com






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