| Abstract: | 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. |
