title: Brain-targeted chemical delivery of [Leu2, Pip3]-TRH: synthesis and biological evaluation.
abstract: A chemical targeting system for [Leu2, Pip3]-TRH (Gln,Leu,Pip) was synthesized in order to allow its specific delivery to the central nervous system (CNS). Sequential metabolism of the obtained 'packaged' chemical delivery system, (CDS), DHT-Pro-Pro-Gln-Leu-Pip-OCh, should yield a 'locked-in' precursor following the oxidative conversion of the dihydrotrigonellyl (DHT) to the trigonellyl (T+) moiety, followed by removal of the cholesteryl function and cleavage of the T+-Pro-Pro by prolyl endopeptidase. The antagonism of barbiturate-induced sleeping time was used to assess the activity of the CDS. The sleeping time after administration of vehicle and [Leu2]-TRH was 100.5 +/- 6.3 min, and 78.2 +/- 4.7 min, respectively. The [Leu2, Pip3]-TRH-CDS showed a significant decrease in sleeping time (58.2 +/- 3.4 min) compared to the vehicle or [Leu2]-TRH. These results indicate successful brain delivery of the precursor construct, and an effective release of the active GlnLeuPip in the brain.
authors.affiliation: Center for Drug Discovery, University of Florida, Gainesville 32611, USA.
authors.forename: S H
authors.initials: SH
authors.lastname: Yoon
authors.forename: J
authors.initials: J
authors.lastname: Wu
authors.forename: W M
authors.initials: WM
authors.lastname: Wu
authors.forename: L
authors.initials: L
authors.lastname: Prokai
authors.forename: N
authors.initials: N
authors.lastname: Bodor
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000378:metabolism*; D051379:Mice; D012890:Sleep / Q000187:drug effects; D013973:Thyrotropin-Releasing Hormone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: C414942:thyrotropin-releasing hormone, Leu(2)-Pip(3)-; D013973:Thyrotropin-Releasing Hormone