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

J Med Chem. 2004 Nov 18;47(24):6025-33. doi: 10.1021/jm020531t.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acetylcholine / metabolism
  • Animals
  • Brain / metabolism*
  • Central Nervous System Stimulants / chemical synthesis*
  • Central Nervous System Stimulants / chemistry
  • Central Nervous System Stimulants / pharmacology
  • Drug Stability
  • Hippocampus / metabolism
  • Histidine / chemistry*
  • In Vitro Techniques
  • Mass Spectrometry
  • Membranes, Artificial
  • Mice
  • Microdialysis
  • Permeability
  • Prodrugs / chemical synthesis*
  • Prodrugs / pharmacology
  • Pyridinium Compounds / chemical synthesis*
  • Pyridinium Compounds / chemistry
  • Pyridinium Compounds / pharmacology
  • Radioligand Assay
  • Rats
  • Structure-Activity Relationship
  • Thyrotropin-Releasing Hormone / analogs & derivatives*
  • Thyrotropin-Releasing Hormone / chemical synthesis*
  • Thyrotropin-Releasing Hormone / chemistry
  • Thyrotropin-Releasing Hormone / pharmacokinetics
  • Thyrotropin-Releasing Hormone / pharmacology
  • Tissue Distribution


  • 3-(aminocarbonyl)-1-(3-(2-(aminocarbonyl)pyrrolidin-1-yl)-3-oxo-2-(((5-oxopyrrolidin-2-yl)carbonyl)amino)propyl)pyridinium
  • Central Nervous System Stimulants
  • Membranes, Artificial
  • Prodrugs
  • Pyridinium Compounds
  • Histidine
  • Thyrotropin-Releasing Hormone
  • Acetylcholine