Centrally acting and metabolically stable thyrotropin-releasing hormone analogues by replacement of histidine with substituted pyridinium.
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.
Prokai
Laszlo
L
Department of Medicinal Chemistry, Department of Pharmacology and Therapeutics, and The McKnight Brain Institute, University of Florida, Gainesville, Florida 32610, USA. lprokai@grove.ufl.edu
Prokai-Tatrai
Katalin
K
Zharikova
Alevtina D
AD
Nguyen
Vien
V
Perjesi
Pal
P
Stevens
Stanley M
SM
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism*; D000697:Central Nervous System Stimulants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004355:Drug Stability; D006624:Hippocampus / Q000378:metabolism; D006639:Histidine / Q000737:chemistry*; D066298:In Vitro Techniques; D013058:Mass Spectrometry; D008567:Membranes, Artificial; D051379:Mice; D017551:Microdialysis; D010539:Permeability; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology; D011726:Pyridinium Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D013329:Structure-Activity Relationship; D013973:Thyrotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D014018:Tissue Distribution
C494558:3-(aminocarbonyl)-1-(3-(2-(aminocarbonyl)pyrrolidin-1-yl)-3-oxo-2-(((5-oxopyrrolidin-2-yl)carbonyl)amino)propyl)pyridinium; D000697:Central Nervous System Stimulants; D008567:Membranes, Artificial; D011355:Prodrugs; D011726:Pyridinium Compounds; D006639:Histidine; D013973:Thyrotropin-Releasing Hormone; D000109:Acetylcholine