Linked Life Data

12781338

Source:http://linkedlifedata.com/resource/pubmed/id/12781338

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
11
pubmed:dateCreated
2003-6-3
pubmed:abstractText
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 K(i) 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 K(i) 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.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
0006-2952
pubmed:author
pubmed:issnType
Print
pubmed:day
1
pubmed:volume
65
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1867-74
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed:year
2003
pubmed:articleTitle
Monoamine oxidase A inhibitory potency and flavin perturbation are influenced by different aspects of pirlindole inhibitor structure.
pubmed:affiliation
Centre for Biomolecular Sciences, University of St. Andrews, North Haugh, St. Andrews, Fife KY16 9ST, UK.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't