Design, synthesis, and biological evaluation of novel, centrally-acting thyrotropin-releasing hormone analogues

Katalin Prokai-Tatrai, Pál Perjési, Alevtina D. Zharikova, Xiaoxu Li, Laszlo Prokai

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)2171-2174
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume12
Issue number16
DOIs
StatePublished - 19 Aug 2002

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