Design and exploratory neuropharmacological evaluation of novel thyrotropin-releasing hormone analogs and their brain-targeting bioprecursor prodrugs

Katalin Prokai-Tatrai, Vien Nguyen, Szabolcs Szarka, Krisztina Konya, Laszlo Prokai

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Efforts to take advantage of the beneficial activities of thyrotropin-releasing hormone (TRH) in the brain are hampered by its poor metabolic stability and lack of adequate central nervous system bioavailability. We report here novel and metabolically stable analogs that we derived from TRH by replacing its amino-terminal pyroglutamyl (pGlu) residue with pyridinium-containing moieties. Exploratory studies have shown that the resultant compounds were successfully delivered into the mouse brain after systemic administration via their bioprecursor prodrugs, where they manifested neuropharmacological responses characteristic of the endogenous parent peptide. On the other hand, the loss of potency compared to TRH in a model testing antidepressant-like effect with a simultaneous preservation of analeptic activity has been observed, when pGlu was replaced with trigonelloyl residue. This finding may indicate an opportunity for designing TRH analogs with potential selectivity towards cholinergic effects.

Original languageEnglish
Pages (from-to)318-328
Number of pages11
JournalPharmaceutics
Volume5
Issue number2
DOIs
StatePublished - 22 May 2013

Fingerprint

Thyrotropin-Releasing Hormone
Prodrugs
Brain
Central Nervous System Stimulants
Cholinergic Agents
Antidepressive Agents
Biological Availability
Central Nervous System
Peptides

Keywords

  • Analeptic effect
  • Antidepressant-like activity
  • Bioprecursor prodrug
  • Brain-targeting delivery
  • Synthetic peptide analog
  • Thyrotropin-releasing hormone

Cite this

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abstract = "Efforts to take advantage of the beneficial activities of thyrotropin-releasing hormone (TRH) in the brain are hampered by its poor metabolic stability and lack of adequate central nervous system bioavailability. We report here novel and metabolically stable analogs that we derived from TRH by replacing its amino-terminal pyroglutamyl (pGlu) residue with pyridinium-containing moieties. Exploratory studies have shown that the resultant compounds were successfully delivered into the mouse brain after systemic administration via their bioprecursor prodrugs, where they manifested neuropharmacological responses characteristic of the endogenous parent peptide. On the other hand, the loss of potency compared to TRH in a model testing antidepressant-like effect with a simultaneous preservation of analeptic activity has been observed, when pGlu was replaced with trigonelloyl residue. This finding may indicate an opportunity for designing TRH analogs with potential selectivity towards cholinergic effects.",
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Design and exploratory neuropharmacological evaluation of novel thyrotropin-releasing hormone analogs and their brain-targeting bioprecursor prodrugs. / Prokai-Tatrai, Katalin; Nguyen, Vien; Szarka, Szabolcs; Konya, Krisztina; Prokai, Laszlo.

In: Pharmaceutics, Vol. 5, No. 2, 22.05.2013, p. 318-328.

Research output: Contribution to journalArticle

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