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Yoon SH, Wu J, Wu WM, Prokai L, Bodor N: Brain-targeted chemical delivery of [Leu2, Pip3]-TRH: synthesis and biological evaluation. Bioorg Med Chem. 2000 May;8(5):1059-63.
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. |
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