TY - JOUR
T1 - Brain-targeted chemical delivery of [Leu2, Pip3]-TRH
T2 - Synthesis and biological evaluation
AU - Yoon, Sung Hwa
AU - Wu, Jiaxiang
AU - Wu, Whei Mei
AU - Prokai, Laszlo
AU - Bodor, Nicholas
PY - 2000/5/1
Y1 - 2000/5/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0034076459&partnerID=8YFLogxK
U2 - 10.1016/S0968-0896(00)00043-2
DO - 10.1016/S0968-0896(00)00043-2
M3 - Article
C2 - 10882017
AN - SCOPUS:0034076459
VL - 8
SP - 1059
EP - 1063
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
SN - 0968-0896
IS - 5
ER -