Inhibition of catechol-O-methyltransferase by 1-vinyl derivatives of nitrocatechols and nitroguaiacols: Kinetics of the irreversible inhibition by 3-(3-hydroxy-4-methoxy-5-nitro benzylidene)-2,4-pentanedione

摘要: It is well known that activated alkene derivatives react with thiol groups according to a Michael's addition reaction. On the basis of presence at least one group essential for activity catechol-O-methyltransferase (COMT), several 1-vinyl nitrocatechol and nitroguaiacol were synthesized tested as potential irreversible active site-directed inhibitors COMT. All products potent partially purified pig liver However, inhibition was reversible in most cases, exception 3-(3-hydroxy-4-methoxy-5-nitrobenzylidene)-2,4-pentanedione (compound 2) which inhibited COMT an manner. When measured function length time pre-incubation 2, biphasic kinetics observed, suggesting modification two are activity. The analysis parts curve inhibitor concentration showed compound 2 modified more reactive non-specific manner, while it behaved on second slow-reacting group. Importantly, saturating S-adenosyl-L-methionine (AdoMet) mixture gave pseudo-first order kinetics, total protection Magnesium ions had no effect by AdoMet. In 3,5-dinitrocatechol (DNC) slight observed; when inactivation both analysed independently, specifically detected, reaction other faster DNC. AdoMet DNC present, not reacting located or near site.