Trapping of metabolically generated electrophilic species with cyanide ion: metabolism of methapyrilene
| Autor: | Bert Ho, R. Ziegler, Neal Castagnoli |
|---|---|
| Rok vydání: | 1981 |
| Předmět: |
Male
Chromatography Gas Magnetic Resonance Spectroscopy Methapyrilene Aminopyridines In Vitro Techniques Medicinal chemistry chemistry.chemical_compound Amide Drug Discovery medicine Organic chemistry Moiety Animals Sodium cyanide Biotransformation Cyanides Iminium Oxidative deamination chemistry Electrophile Microsomes Liver Molecular Medicine Amine gas treating Rabbits NADP medicine.drug |
| Zdroj: | Journal of medicinal chemistry. 24(10) |
| ISSN: | 0022-2623 |
| Popis: | The popular antihistamine methapyrilene [N,N-dimethyl-N'-(2-pyridyl)-N'-(2-thienylmethyl)-1,2-ethanediamine] recently has been shown to be a potent hepatocarcinogen. Metabolic studies with rabbit liver 100000g microsomal preparations have resulted in the partial characterization of the in vitro metabolic profile of methapyrilene. Evidence for the formation of the N-oxide and the three possible carbinolamines resulting from the NADPH-dependent oxidation of the (dimethylamino)ethyl side chain nitrogen and carbon atoms of methapyrilene is presented. Attempts to trap iminium ion intermediates with electrophilic alkylating potential by coincubating methapyrilene with sodium cyanide have led to the isolation of N-(cyanomethyl)normethapyrilene. The possibility of characterizing the iminium ion intermediate that would result from the oxidative deamination of the dimethylamino moiety was precluded by the chemical instability of the corresponding alpha-cyano amine, which undergoes a spontaneous retro-Michael reaction and hydrolysis to the corresponding amide. The results are discussed in terms of the metabolic activation of methapyrilene to potential alkylating species. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|