Design, synthesis, and biological evaluation of novel, centrally-Acting thyrotropin-Releasing hormone analogues

• Published in: Bioorganic & medicinal chemistry letters 2002-08, Vol.12 (16), p.2171-2174
• Main Authors: Prokai-Tatrai, Katalin, Perjési, Pál, Zharikova, Alevtina D, Li, Xiaoxu, Prokai, Laszlo
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Central Nervous System Stimulants - chemical synthesis; Central Nervous System Stimulants - chemistry; Central Nervous System Stimulants - metabolism; Central Nervous System Stimulants - pharmacology; Drug Antagonism; Drug Design; Medical sciences; Mice; Molecular Structure; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pentobarbital - pharmacology; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Prodrugs - chemical synthesis; Prodrugs - chemistry; Prodrugs - metabolism; Receptors, Thyrotropin-Releasing Hormone - antagonists & inhibitors; Sleep - drug effects; Thyrotropin-Releasing Hormone - analogs & derivatives; Thyrotropin-Releasing Hormone - chemical synthesis; Thyrotropin-Releasing Hormone - metabolism; Thyrotropin-Releasing Hormone - pharmacology
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(02)00368-2

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. Solid-phase synthesis and analeptic effect evaluated after intravenous injection of their 1,4-dihydropyridine prodrug forms ( 3a– d) of novel TRH analogues ( 2a– d) having central pyridinium moiety are reported.