title: Improved brain uptake and pharmacological activity profile of morphine-6-glucuronide using a peptide vector-mediated strategy.
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 (ED(50) of 1.87 versus 8.74 micromol/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.
authors.affiliation: Synt:em, Parc Scientifique Georges Besse, Nîmes, France. jtemsamani@syntem.com
authors.forename: Jamal
authors.initials: J
authors.lastname: Temsamani
authors.forename: Cécile
authors.initials: C
authors.lastname: Bonnafous
authors.forename: Christophe
authors.initials: C
authors.lastname: Rousselle
authors.forename: Yannik
authors.initials: Y
authors.lastname: Fraisse
authors.forename: Philippe
authors.initials: P
authors.lastname: Clair
authors.forename: Luc-André
authors.initials: LA
authors.lastname: Granier
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Rees
authors.forename: Michel
authors.initials: M
authors.lastname: Kaczorek
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Scherrmann
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods*; D008297:Male; D051379:Mice; D009022:Morphine Derivatives / Q000008:administration & dosage / Q000378:metabolism*; D009842:Oligopeptides / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000378:metabolism*; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods
chemical_list: D009022:Morphine Derivatives; D009842:Oligopeptides; C035349:morphine-6-glucuronide