TRANSFORMATION OF MONOAMINE OXIDASE-B PRIMARY AMINE SUBSTRATES INTO TIME-DEPENDENT INHIBITORS - TERTIARY AMINE HOMOLOGS OF PRIMARY AMINE SUBSTRATES

被引:20
作者
DING, CZ
LU, XL
NISHIMURA, K
SILVERMAN, RB
机构
[1] NORTHWESTERN UNIV,DEPT CHEM,EVANSTON,IL 60208
[2] NORTHWESTERN UNIV,DEPT BIOCHEM MOLEC BIOL & CELL BIOL,EVANSTON,IL 60208
关键词
D O I
10.1021/jm00064a004
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
A family of N-methylated and N,N-dimethylated alkyl and arylalkylamines was prepared and more than half of the analogues were shown to be time-dependent pseudo-first-order inhibitors of monoamine oxidase-B. Some of the time-dependent inactivators were reversible and others were irreversible with respect to prolonged dialysis following inactivation. Partition ratios ranged from zero to 11 000. These results are rationalized in terms of a combination of an inductive effect and a stereoelectronic effect as a result of hindered rotation of an active site covalent adduct. A molecular mechanics calculation indicates that there is at least 10 kcal/mol of torsional energy to be overcome in order for the enzyme adduct to be released. These findings show that tertiary amine homologues of primary amine substrates of monoamine oxidase are time-dependent inhibitors, and this should be useful in the design of new inactivators of this enzyme.
引用
收藏
页码:1711 / 1715
页数:5
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