Contribution of pi-electrons to the inhibition of S-adenosyl-L-methionine decarboxylase by aromatic tricyclic compounds.
Eleven structural analogs with norharmane (9H-pyrido [3, 4-b] indole) as the basic structure were used to study structure-activity relations of adenosyl-methionine decarboxylase inhibition by this type of compounds. All analogs with an intact or 3,4-dihydrogenated pyrido ring inhibited the enzyme competitively with apparent Kis at the micromolar range, but complete hydrogenation of the pyrido moiety abolished the inhibition. This indicates that a suitable arrangement of pi-electrons is an essential structural feature in the process. Strongest inhibitors (Ki approximately 10-5M) were compounds methoxy or hydroxy groups in positions 6 or 7 of the indole moiety, suggesting that polarizing groups containing atoms with free electron pairs also are important in the interaction. The results offer a new viewpoint when action mechanisms of the known adenosylmethionine decarboxylase inhibitors are evaluated and they may prove useful when new inhibitors to the enzyme are designed.
D012437:Adenosylmethionine Decarboxylase / Q000037:antagonists & inhibitors*; D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000201:enzymology; D002243:Carbolines; D002262:Carboxy-Lyases / Q000037:antagonists & inhibitors*; D004583:Electrons; D006247:Harmine / Q000031:analogs & derivatives / Q000494:pharmacology*; D007700:Kinetics; D051379:Mice; D013329:Structure-Activity Relationship
D000470:Alkaloids; D002243:Carbolines; D006247:Harmine; C010262:norharman; D002262:Carboxy-Lyases; D012437:Adenosylmethionine Decarboxylase