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

1
Department of Molecular Biology and Immunology, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107-2699, USA
2
Department of Pharmaceutical Sciences, UNT System College of Pharmacy, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107-2699, USA
*
Author to whom correspondence should be addressed.
Current address: Department of Organic Chemistry, University of Debrecen, H-4032 Debrecen, Egyetem tér 1, Hungary
Pharmaceutics 2013, 5(2), 318-328; https://doi.org/10.3390/pharmaceutics5020318
Received: 21 March 2013 / Revised: 7 May 2013 / Accepted: 10 May 2013 / Published: 22 May 2013
(This article belongs to the Special Issue Prodrugs)
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. View Full-Text
Keywords: bioprecursor prodrug; brain-targeting delivery; thyrotropin-releasing hormone; synthetic peptide analog; analeptic effect; antidepressant-like activity bioprecursor prodrug; brain-targeting delivery; thyrotropin-releasing hormone; synthetic peptide analog; analeptic effect; antidepressant-like activity
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MDPI and ACS Style

Prokai-Tatrai, K.; Nguyen, V.; Szarka, S.; Konya, K.; Prokai, L. Design and Exploratory Neuropharmacological Evaluation of Novel Thyrotropin-Releasing Hormone Analogs and Their Brain-Targeting Bioprecursor Prodrugs. Pharmaceutics 2013, 5, 318-328. https://doi.org/10.3390/pharmaceutics5020318

AMA Style

Prokai-Tatrai K, Nguyen V, Szarka S, Konya K, Prokai L. Design and Exploratory Neuropharmacological Evaluation of Novel Thyrotropin-Releasing Hormone Analogs and Their Brain-Targeting Bioprecursor Prodrugs. Pharmaceutics. 2013; 5(2):318-328. https://doi.org/10.3390/pharmaceutics5020318

Chicago/Turabian Style

Prokai-Tatrai, Katalin, Vien Nguyen, Szabolcs Szarka, Krisztina Konya, and Laszlo Prokai. 2013. "Design and Exploratory Neuropharmacological Evaluation of Novel Thyrotropin-Releasing Hormone Analogs and Their Brain-Targeting Bioprecursor Prodrugs" Pharmaceutics 5, no. 2: 318-328. https://doi.org/10.3390/pharmaceutics5020318

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