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.
Highlights
Our laboratory has been involved in medicinal chemistry-driven research with attention to facilitating drug delivery of central nervous system (CNS) agents via prodrug approaches.Thyrotropin-releasing hormone (TRH), a small peptide, has been one of the main focuses in this regard [1,2,3,4,5]
In vitro stability studies in freshly made mouse brain homogenate and plasma [3,4,5,16], respectively, showed that 2 and 3 were metabolically stable; no significant degradations of the compounds were detected within 2 h by reversed-phase high-performance liquid chromatography (RP-HPLC)
We have confirmed that when the central histidyl residue (His) is replaced in the thyrotropin-releasing hormone (TRH) sequence with pyridinium-based amino acids, the resultant TRH analogs were metabolically stable [2,3]
Summary
Katalin Prokai-Tatrai 1,2,*, Vien Nguyen 1, Szabolcs Szarka 1, Krisztina Konya 1,† and Laszlo Prokai 1.
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