Design, synthesis, and biological evaluation of novel, centrally-acting thyrotropin-releasing hormone analogues.
Novel, metabolically stable and centrally acting TRH analogues with substituted pyridinium moieties replacing the [His(2)] residue of the endogenous peptide were prepared by solid-phase Zincke reaction. The 1,4-dihydropyridine prodrugs of these analogues obtained after reducing the pyridinium moiety were able to reach the brain and maintain a sustained concentration of the charged, degradation-resistant analogues formed after enzymatic oxidation of the prodrug, as manifested by the analeptic action measured in mice. Among the four analogues reported, compound 2a showed the highest potency and longest duration of action in reducing the pentobarbital-induced sleeping time compared to the parent TRH. No binding to the endocrine TRH-receptor was measured for 2a; thus, this compound emerged as a potent, centrally acting TRH analogue.
Prokai-Tatrai
Katalin
K
Center for Drug Discovery, College of Pharmacy, University of Florida, Gainesville, FL 32610-0497, USA. lprokai@grove.ufl.edu
Perjési
Pál
P
Zharikova
Alevtina D
AD
Li
Xiaoxu
X
Prokai
Laszlo
L
D000818:Animals; D000697:Central Nervous System Stimulants / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004336:Drug Antagonism; D015195:Drug Design; D051379:Mice; D015394:Molecular Structure; D010424:Pentobarbital / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D018025:Receptors, Thyrotropin-Releasing Hormone / Q000037:antagonists & inhibitors; D012890:Sleep / Q000187:drug effects; D013973:Thyrotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology
D000697:Central Nervous System Stimulants; D011355:Prodrugs; D018025:Receptors, Thyrotropin-Releasing Hormone; D013973:Thyrotropin-Releasing Hormone; D010424:Pentobarbital