Brain-targeted chemical delivery of [Leu2, Pip3]-TRH: Synthesis and biological evaluation

Sung Hwa Yoon, Jiaxiang Wu, Whei Mei Wu, Laszlo Prokai, Nicholas Bodor

Research output: Contribution to journalArticle

15 Scopus citations

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. (C) 2000 Elsevier Science Ltd.

Original languageEnglish
Pages (from-to)1059-1063
Number of pages5
JournalBioorganic and Medicinal Chemistry
Volume8
Issue number5
DOIs
StatePublished - 1 May 2000

Fingerprint Dive into the research topics of 'Brain-targeted chemical delivery of [Leu<sup>2</sup>, Pip<sup>3</sup>]-TRH: Synthesis and biological evaluation'. Together they form a unique fingerprint.

  • Cite this