A Pyridinium-substituted Analog of the TRH-like Tripeptide pGlu-Glu- Pro-NH2 and its Prodrugs as Central Nervous System Agents

K.      Prokai-Tatrai; M.      Teixido; V.      Nguyen; A.   D.   Zharikova; L.      Prokai

doi:10.2174/1573406053175256

Abstract

A metabolically stable and centrally acting analog of pGlu-Glu-Pro-NH2 ([Glu2]TRH, a tripeptide structurally related to TRH (thyrotropin-releasing hormone)) was designed by replacing the amino-terminal pyroglutamyl residue with a pyridinium moiety. The analeptic action of the analog was used to optimize the efficacy of this novel CNS agent when administered intravenously in its CNS-permeable prodrug forms obtained via the reduction of the pyridinium moiety to the nonionic dihydropyridine and esterifying the central Glu with various alcohols. The maximum effect in antagonizing pentobarbital-induced narcosis in mice was achieved with the hexyl ester that was used subsequently for a comparative evaluation with a prodrug of the parent neuropeptide in the Porsolt swim test as a paradigm for antidepressant effect. The novel analog maintained its antidepressant potency but showed reduced analeptic action compared to [Glu2]TRH; thus, an increase in the selectivity of CNS-action was obtained by the incorporation of the pyridinium moiety.

Keywords: [glu2]trh, central nervous system permeable prodrugs, analeptic effect, antidepressant, porsolt swim test, immobilized artificial membrane chromatography

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