PT  - JOURNAL ARTICLE
AU  - Jamal Temsamani
AU  - Cécile Bonnafous
AU  - Christophe Rousselle
AU  - Yannik Fraisse
AU  - Philippe Clair
AU  - Luc-André Granier
AU  - Anthony R. Rees
AU  - Michel Kaczorek
AU  - Jean-Michel Scherrmann
TI  - Improved Brain Uptake and Pharmacological Activity Profile of Morphine-6-Glucuronide Using a Peptide Vector-Mediated Strategy
AID  - 10.1124/jpet.104.081000
DP  - 2005 May 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 712--719
VI  - 313
IP  - 2
4099  - http://jpet.aspetjournals.org/content/313/2/712.short
4100  - http://jpet.aspetjournals.org/content/313/2/712.full
SO  - J Pharmacol Exp Ther2005 May 01; 313
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics