TY - JOUR
T1 - Design, synthesis, and biological evaluation of novel, centrally-acting thyrotropin-releasing hormone analogues
AU - Prokai-Tatrai, Katalin
AU - Perjési, Pál
AU - Zharikova, Alevtina D.
AU - Li, Xiaoxu
AU - Prokai, Laszlo
N1 - Funding Information:
The authors wish to thank to Olena Glushakova for her technical assistance in animal experiments. This research has been supported by a grant from the National Institutes of Health (MH59380).
PY - 2002/8/19
Y1 - 2002/8/19
N2 - Novel, metabolically stable and centrally acting TRH analogues with substituted pyridinium moieties replacing the [His2] residue of the endogenous peptide were prepared by solid-phase Zincke reaction. The 1,4-dihydropyridine prodrugs of these analogues obtained after reducing the pyridinium moiety were able to reach the brain and maintain a sustained concentration of the charged, degradation-resistant analogues formed after enzymatic oxidation of the prodrug, as manifested by the analeptic action measured in mice. Among the four analogues reported, compound 2a showed the highest potency and longest duration of action in reducing the pentobarbital-induced sleeping time compared to the parent TRH. No binding to the endocrine TRH-receptor was measured for 2a; thus, this compound emerged as a potent, centrally acting TRH analogue.
AB - Novel, metabolically stable and centrally acting TRH analogues with substituted pyridinium moieties replacing the [His2] residue of the endogenous peptide were prepared by solid-phase Zincke reaction. The 1,4-dihydropyridine prodrugs of these analogues obtained after reducing the pyridinium moiety were able to reach the brain and maintain a sustained concentration of the charged, degradation-resistant analogues formed after enzymatic oxidation of the prodrug, as manifested by the analeptic action measured in mice. Among the four analogues reported, compound 2a showed the highest potency and longest duration of action in reducing the pentobarbital-induced sleeping time compared to the parent TRH. No binding to the endocrine TRH-receptor was measured for 2a; thus, this compound emerged as a potent, centrally acting TRH analogue.
UR - http://www.scopus.com/inward/record.url?scp=0037136022&partnerID=8YFLogxK
U2 - 10.1016/S0960-894X(02)00368-2
DO - 10.1016/S0960-894X(02)00368-2
M3 - Article
C2 - 12127530
AN - SCOPUS:0037136022
SN - 0960-894X
VL - 12
SP - 2171
EP - 2174
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
IS - 16
ER -