Centrally acting and metabolically stable thyrotropin-releasing hormone analogues by replacement of histidine with substituted pyridinium

Laszlo Prokai, Katalin Prokai-Tatrai, Alevtina D. Zharikova, Vien Nguyen, P. Perjési, Stanley M. Stevens

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Metabolically stable and centrally acting thyrotropin-releasing hormone (TRH) analogues were designed by replacing the central histidine with substituted pyridinium moieties. Their analeptic and acetylcholine-releasing actions were evaluated to assess their potency as central nervous system (CNS) agents. A strong experimental connection between these two CNS-mediated actions of the TRH analogues was obtained in subject animals. The analogue 3-(aminocarbonyl)-1-(3-[2-(aminocarbonyl)pyrrolidin-1-yl]-3-oxo-2-{[(5- oxopyrrolidin-2-yl)carbonyl]amino}propyl)-pyridinium (1a) showed the highest (TRH-equivalent) potency and longest, dose-dependent duration of action from a series of homologous compounds in antagonizing pentobarbital-induced narcosis when administered intravenously in its CNS-permeable prodrug form (2a) obtained via reduction of the pyridinium moiety to the nonionic dihydropyridine. The maximum change in hippocampal acetylcholine concentration upon perfusion of the pyridinium-containing tripeptides into the hippocampus of rats was also achieved with 1a. No binding to the endocrine TRH receptor was measured for the TRH analogues reported here; therefore, our design afforded a novel lead for centrally acting TRH analogues. We have also demonstrated the benefits of the prodrug approach on the pharmacokinetics and brain uptake/retention of pyridinium-containing TRH analogues (measured by in vivo microdialysis sampling) upon systemic administration.

Original languageEnglish
Pages (from-to)6025-6033
Number of pages9
JournalJournal of Medicinal Chemistry
Volume47
Issue number24
DOIs
Publication statusPublished - Nov 18 2004

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Thyrotropin-Releasing Hormone
Histidine
Prodrugs
Neurology
Acetylcholine
Central Nervous System
Thyrotropin Releasing Hormone Receptors
Central Nervous System Agents
Central Nervous System Stimulants
Stupor
Pharmacokinetics
Microdialysis
Pentobarbital
Rats
Hippocampus
Brain
Animals
Perfusion
Sampling

ASJC Scopus subject areas

  • Organic Chemistry

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Centrally acting and metabolically stable thyrotropin-releasing hormone analogues by replacement of histidine with substituted pyridinium. / Prokai, Laszlo; Prokai-Tatrai, Katalin; Zharikova, Alevtina D.; Nguyen, Vien; Perjési, P.; Stevens, Stanley M.

In: Journal of Medicinal Chemistry, Vol. 47, No. 24, 18.11.2004, p. 6025-6033.

Research output: Contribution to journalArticle

Prokai, Laszlo ; Prokai-Tatrai, Katalin ; Zharikova, Alevtina D. ; Nguyen, Vien ; Perjési, P. ; Stevens, Stanley M. / Centrally acting and metabolically stable thyrotropin-releasing hormone analogues by replacement of histidine with substituted pyridinium. In: Journal of Medicinal Chemistry. 2004 ; Vol. 47, No. 24. pp. 6025-6033.
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