title: A pyridinium-substituted analog of the TRH-like tripeptide pGlu-Glu-Pro-NH2 and its prodrugs as central nervous system agents.
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.
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Florida, 1600 Archer Road, Gainesville, FL 32610-0485, USA.
authors.forename: K
authors.initials: K
authors.lastname: Prokai-Tatrai
authors.forename: M
authors.initials: M
authors.lastname: Teixido
authors.forename: V
authors.initials: V
authors.lastname: Nguyen
authors.forename: A D
authors.initials: AD
authors.lastname: Zharikova
authors.forename: L
authors.initials: L
authors.lastname: Prokai
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000187:drug effects*; D002491:Central Nervous System Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D066298:In Vitro Techniques; D051379:Mice; D015394:Molecular Structure; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011726:Pyridinium Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives* / Q000737:chemistry; D013329:Structure-Activity Relationship; D013550:Swimming; D013973:Thyrotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000737:chemistry
chemical_list: D002491:Central Nervous System Agents; D011355:Prodrugs; D011726:Pyridinium Compounds; D013973:Thyrotropin-Releasing Hormone; C059697:pyroglutamyl-glutamyl-proline amide; D011761:Pyrrolidonecarboxylic Acid