Article

Design and Exploratory Neuropharmacological Evaluation of Novel Thyrotropin-Releasing Hormone Analogs and Their Brain-Targeting Bioprecursor Prodrugs

Department of Molecular Biology and Immunology, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107-2699, USA
Pharmaceutics 05/2013; 5(2):318-328. DOI: 10.3390/pharmaceutics5020318
Source: PubMed

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.

Download full-text

Full-text

Available from: Szabolcs Szarka, Feb 20, 2014
1 Follower
 · 
78 Views
  • Source
    [Show abstract] [Hide abstract]
    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.
    Journal of Medicinal Chemistry 11/2004; 47(24):6025-33. DOI:10.1021/jm020531t · 5.48 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Besides its well-known endocrine role in the thyroid system, thyrotropin-releasing hormone (L-pyroglutamyl-L-histidyl-L-prolinamide) has been long recognized as a modulatory neuropeptide. After a brief overview of the extrahypothalamic and receptor distribution, and of the neurophysiological, neuropharmacological and neurochemical effects of this tripeptide, this review discusses efforts devoted to enhance therapeutically beneficial central nervous system effects via structural modifications of the endogenous peptide. An enormous array of maladies affecting the brain and the spinal cord has been a potential target for therapeutic interventions involving agents derived from thyrotropin-releasing hormone as a molecular lead. Successful development of several centrally active analogues and recent accounts of efforts aimed at improving metabolic stability, selectivity and bioavailability are highlighted.
    Fortschritte der Arzneimittelforschung. Progress in drug research. Progrès des recherches pharmaceutiques 02/2002; 59:133-69.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Novel, metabolically stable and centrally acting TRH analogues with substituted pyridinium moieties replacing the [His(2)] 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.
    Bioorganic & Medicinal Chemistry Letters 09/2002; 12(16):2171-4. DOI:10.1016/S0960-894X(02)00368-2 · 2.33 Impact Factor
Show more