INHIBITION OF MAO A AND MAO B BY TOBACCO ALKALOIDS

描述(申请人摘要)： 本申请中提出的研究旨在确定 烟草生物碱(S)-尼古丁和(R，S)-N-甲基可那滨可能有助于 MAO-A和MAO-B活性分别下降28%和40% 通过PET分析在吸烟者的大脑中观察到。我们的注意力集中在 亚胺离子代谢物潜在缓蚀剂性能的研究 通过细胞色素P450催化氧化这些生物碱，因为(1)我们 有初步证据表明，β1‘，5’-亚胺离子代谢物 (S)-尼古丁是MAO-B的抑制剂，(2)约70%的(S)-尼古丁(和， 根据推断，结构上相关的烟草生物碱)通过这种方式代谢 途径和(3)间接证据支持(S)尼古丁是 由脑酶代谢成亚胺离子物种。具体目标 将进行的工作包括(1)衬底的表征和 纯化的MAO-A与目标化合物的缓蚀剂性能 MAO-B；(2)体内MAO-A和MAO-B抑制剂检测 (S)-尼古丁和(R，S)-N-甲基那他滨在啮齿动物模型中的性质 (3)这些化合物在大鼠体内的代谢行为 和狒狒脑线粒体和微粒体制剂；和(4)一个 化学活性中间体潜在形成的研究 (S)-尼古丁和(R，S)-N-甲基纳他滨在体内和脑匀浆中的分布 通过确定与代谢有关的共价加合物的形成 肝脏和大脑的大分子。我们认为这些研究应该 确定或排除这些化合物在调解 吸烟者大脑中MAO-A和MAO-B活性的丧失。

DESCRIPTION (Applicant's Abstract): The studies proposed in this application are designed to determine if the tobacco alkaloids (S)-nicotine and (R,S)-N-methylanatabine may contribute to the 28% and 40% decrements, respectively, in MAO-A and MAO-B activity observed in the brains of smokers by PET analysis. Our attention is focused on the potential inhibitor properties of iminium ion metabolites generated by the cytochrome-P450 catalyzed oxidation of these alkaloids since (1) we have preliminary evidence that the delta 1',5' -iminium ion metabolite of (S)-nicotine is an inhibitor of MAO-B, (2) about 70% of (S)-nicotine (and, by inference, structurally related tobacco alkaloids) is metabolized by this pathway and (3) indirect evidence supports the proposal that (S)-nicotine is metabolized by brain enzymes to the iminium ion species. The specific aims that will be pursued include (1) the characterization of the substrate and inhibitor properties of the compounds of interest with purified MAO-A and MAO-B; (2) an examination of the in vivo MAO-A and MAO-B inhibitor properties of (S)-nicotine and (R,S)-N-methylanatabine in a rodent model; (3) the characterization of the metabolic fate of these compounds using rat and baboon brain mitochondrial and microsomal preparations; and (4) an examination of the potential formation of chemically reactive intermediates of (S)-nicotine and (R,S)-N-methylanatabine in vivo and in brain homogenates by determining the metabolically dependent formation of covalent adducts with liver and brain macromolecules. We submit that these studies should establish or rule out a role for these compounds in the mediation of the loss of MAO-A and MAO-B activity in the brains of smokers.