Inactivation of purified human recombinant monoamine oxidases A and B by rasagiline and its analogues
Inactivation of purified human recombinant monoamine oxidases A and B by rasagiline and its analogues
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DOI：
10.1021/jm0310885
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发表时间：
2004-03-25
影响因子：
7.3
通讯作者：
Edmondson, DE
中科院分区：
文献类型：
--
作者：
Hubálek, F;Binda, C;Edmondson, DE
纯化的人重组单胺氧化酶（MAO）A和B被雷沙吉兰[N-炔丙基-1（R）-氨基茚满]及其四种类似物[N-炔丙基-1（S）-氨基茚满（S-PAI）、6-羟基-N-炔丙基-1（R）-氨基茚满（R-HPAI）、N-甲基-N-炔丙基-1（R）-氨基茚满（R-MPAI）、和6-（N-甲基-N-乙基氨甲酰氧基）-N-炔丙基-1（R）-氨基茚满（R-CPAI）]。除R-CPAI外，所有测试化合物均与任一酶的FAD部分形成化学计量的N（5）黄嘌呤加合物。在单胺氧化酶A或单胺氧化酶B失活过程中均不产生H2 O2，这表明共价加成发生在单次转换中。雷沙吉兰对MAO B具有最高的特异性，如与MAO A相比高100倍的抑制效力（k（inact）/K-i）所证明的，其余化合物表现出较低的同工酶特异性。与S-对映体（S-PAI）相比，MAO B和MAO A对R-对映体（雷沙吉兰）的选择性分别高出2500倍和17倍。根据MAO B与雷沙吉兰及其类似物的复合物的晶体学数据，解释了所研究的化合物与MAO A和MAO B的复合物的UV/维斯和CD光谱数据的差异。
The inactivation of purified human recombinant monoamine oxidases (MAO) A and B by rasagiline [N-propargyl-1(R)-aminoindan] and four of its analogues [N-propargyl-1(S)-aminoindan (S-PAI), 6-hydroxy-N-propargyl-1(R)-aminoindan (R-HPAI), N-methyl-N-propargyl-1(R)-aminoindan (R-MPAI), and 6-(N-methyl-N-ethyl carbamoyloxy)-N-propargyl-1(R)-aminoindan (R-CPAI)] has been investigated. All compounds tested, with the exception of R-CPAI, form stoichiometric N(5) flavocyanine adducts with the FAD moiety of either enzyme. No H2O2 is produced during either MAO A or MAO B inactivation, which demonstrates that covalent addition occurs in a single turnover. Rasagiline has the highest specificity for MAO B, as demonstrated by a 100-fold higher inhibition potency (k(inact)/K-i) compared to MAO A, with the remaining compounds exhibiting lower isozyme specificities. MAO B and MAO A are more selective for the R-enantiomer (rasagiline) compared to the S-enantiomer (S-PAI) by 2500-fold and 17-fold, respectively. Differences in UV/vis and CD spectral data of the complexes of the studied compounds with both MAO A and MAO B are interpreted in light of crystallographic data of complexes of MAO B with rasagiline and its analogues.