title: A strategy for delivering peptides into the central nervous system by sequential metabolism.
abstract: Most peptides do not enter the central nervous system because of their hydrophilic character and the presence of peptidolytic enzymes in the lipoidal blood-brain barrier. To achieve brain delivery of a peptide conjugate, an opioid peptide (enkephalin) was placed in a molecular environment that disguises its peptide nature and provides biolabile, lipophilic functions to penetrate the blood-brain barrier by passive transport. The strategy also incorporates a 1,4-dihydrotrigonellinate targetor that undergoes an enzymatically mediated oxidation to a hydrophilic, membrane-impermeable trigonellinate salt. The polar targetorpeptide conjugate that is trapped behind the lipoidal blood-brain barrier is deposited in the central nervous system. Analgesia was observed with "packaged" enkephalin but not with the unmodified peptide or lipophilic peptide precursors.
authors.affiliation: Center for Drug Discovery, College of Pharmacy, J. Hillis Miller Health Center, University of Florida, Gainesville 32610.
authors.forename: N
authors.initials: N
authors.lastname: Bodor
authors.forename: L
authors.initials: L
authors.lastname: Prokai
authors.forename: W M
authors.initials: WM
authors.lastname: Wu
authors.forename: H
authors.initials: H
authors.lastname: Farag
authors.forename: S
authors.initials: S
authors.lastname: Jonalagadda
authors.forename: M
authors.initials: M
authors.lastname: Kawamura
authors.forename: J
authors.initials: J
authors.lastname: Simpkins
mesh_terms: D000595:Amino Acid Sequence; D000626:Aminopeptidases / Q000378:metabolism; D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology*; D001921:Brain / Q000378:metabolism*; D002788:Cholesterol Esters / Q000008:administration & dosage / Q000378:metabolism; D016308:Enkephalin, Leucine-2-Alanine / Q000008:administration & dosage / Q000378:metabolism; D050356:Lipid Metabolism; D013058:Mass Spectrometry; D008969:Molecular Sequence Data; D009249:NADP / Q000378:metabolism; D010455:Peptides / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D011355:Prodrugs / Q000008:administration & dosage* / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012995:Solubility
chemical_list: D002788:Cholesterol Esters; D010455:Peptides; D011355:Prodrugs; D009249:NADP; D016308:Enkephalin, Leucine-2-Alanine; D000626:Aminopeptidases