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
N1 - Funding Information:
S.-H. Yoon is gratefully acknowledges the Korean Research Foundation for the support of the 1996 Professor Dispatch Program abroad. This work was supported by NIH grants R01 NS30616 and P01 AG10485.
PY - 2000/5
Y1 - 2000/5
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 -