Monoamine oxidase A inhibitory potency and flavin perturbation are influenced by different aspects of pirlindole inhibitor structure

Robert M.G. Hynson, Johan Wouters, Rona R. Ramsay

Résultats de recherche: Contribution à un journal/une revueArticleRevue par des pairs

Résumé

Reversible inhibitors of monoamine oxidase A (MAO A) are used as antidepressants. The influence of inhibitors such as pirlindole (pyrazinocarbazole) on the redox co-factor (flavin adenine dinucleotide, FAD) is a key factor in the inhibition. The kinetic, spectral, and thermodynamic changes induced by four closely related pirlindole analogues have been determined to investigate their interaction with the FAD in the active site of MAO A. For a model of flavin-inhibitor stacking, more favourable association would be expected between lumiflavin and the flatter analogues with a double bond at N3, and indeed lower Ki values were found. However, the spectral changes induced by inhibitor binding to MAO A were 45% less for inhibitors with a double bond. Both in the absence and presence of the double bond, compounds with cyclohexyl at C8 induced 85% larger decrease in absorbance at 500nm than did those with a methyl substituent. In contrast, the Ki values for the cyclohexyl compounds were lower, indicating greater affinity despite the lower perturbation of the flavin spectrum. All inhibitors stabilised the semiquinone of the FAD when MAO A was titrated with dithionite and prevented further reduction. These results indicate that the active site of MAO A is far more sensitive to structural variation than would be predicted by the simple flavin stacking model. Further, the independent changes in inhibitory potency and flavin perturbation preclude direct interaction with the flavin as a mode of binding and indicate that inhibitor-protein interactions must be important for inhibition.

langue originaleAnglais
Pages (de - à)1867-1874
Nombre de pages8
journalBiochemical Pharmacology
Volume65
Numéro de publication11
Les DOIs
Etat de la publicationPublié - 1 juin 2003
Modification externeOui

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