Stereoselective inhibition of serotonin transporters by antimalarial compounds.
Stereoselective inhibition of serotonin transporters by antimalarial compounds.
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DOI：
10.1016/j.neuint.2013.10.009
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发表时间：
2014-07
影响因子：
4.2
通讯作者：
Henry LK
中科院分区：
文献类型：
--
作者：
Beckman ML;Pramod AB;Perley D;Henry LK
5-羟色胺（5-HT）转运蛋白（SERT）是一种完整的膜蛋白，其功能是重新摄取神经传递后释放到突触中的5-HT。这种作用是神经元稳态的重要调节机制。先前的研究已经证明，几种临床上重要的抗疟化合物抑制血清素（5-羟色胺，5-HT）再摄取。在这项研究中，我们研究了抗疟抑制5-HT运输在果蝇（dSERT）和人类SERT（hSERT）的电生理，生物化学和计算方法的细节。我们发现，金鸡纳生物碱奎尼丁和辛可宁，具有相同的立体化学约碳8和9，表现出最大的抑制dSERT和hSERT转运功能，而奎宁和辛可尼丁，奎尼丁和辛可宁的对映体，分别是较弱的dSERT和hSERT的抑制剂。此外，已知降低许多抗抑郁药的结合亲和力的SERT突变以立体特异性方式影响金鸡纳生物碱，其中奎宁和辛可宁（8 S，9 R）的类似抑制谱与奎尼丁和辛可宁（8 R，9 S）不同。使用hSERT同源性模型的小分子对接研究预测奎宁和辛可宁结合中央5-HT结合位点（S1），而奎尼丁和辛可宁结合S2位点。总之，这里提供的数据支持金鸡纳生物碱结合到SERT上的两个不同位点，这意味着转运蛋白抑制的不同模式。值得注意的是，SERT的最有效的抗疟抑制剂似乎优先结合S2位点。我们的研究结果提供了重要的见解，这类药物如何可以调节多巴胺能系统，以及确定的化合物，可以区分S1和S2结合位点，并作为新的SERT抑制剂的先导化合物。
The serotonin (5-HT) transporter (SERT) is an integral membrane protein that functions to reuptake 5-HT released into the synapse following neurotransmission. This role serves an important regulatory mechanism in neuronal homeostasis. Previous studies have demonstrated that several clinically important antimalarial compounds inhibit serotonin (5-hydroxytryptamine, 5-HT) reuptake. In this study, we examined the details of antimalarial inhibition of 5-HT transport in both Drosophila (dSERT) and human SERT (hSERT) using electrophysiologic, biochemical and computational approaches. We found that the cinchona alkaloids quinidine and cinchonine, which have identical stereochemistry about carbons 8 and 9, exhibited the greatest inhibition of dSERT and hSERT transporter function whereas quinine and cinchonidine, enantiomers of quinidine and cinchonine, respectively, were weaker inhibitors of dSERT and hSERT. Furthermore, SERT mutations known to decrease the binding affinity of many antidepressants affected the cinchona alkaloids in a stereo-specific manner where the similar inhibitory profiles for quinine and cinchonidine (8S,9R) were distinct from quinidine and cinchonine (8R,9S). Small molecule docking studies with hSERT homology models predict that quinine and cinchonidine bind to the central 5-HT binding site (S1) whereas quinidine and cinchonine bind to the S2 site. Taken together, the data presented here support binding of cinchona alkaloids to two different sites on SERT defined by their stereochemistry which implies separate modes of transporter inhibition. Notably, the most potent antimalarial inhibitors of SERT appear to preferentially bind to the S2 site. Our findings provide important insight related to how this class of drugs can modulate the serotonergic system as well as identify compounds that may discriminate between the S1 and S2 binding sites and serve as lead compounds for novel SERT inhibitors.
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影响因子：
64.8
作者：
BLAKELY, RD;BERSON, HE;BRADLEY, CC
通讯作者：
BRADLEY, CC
影响因子：
4.7
作者：
Beckman, ML;Quick, MW
通讯作者：
Quick, MW
非竞争性ibogaine抑制5-羟色胺和多巴胺转运蛋白的机械基础。
DOI：
10.1074/jbc.m112.343681
发表时间：
2012-05-25
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Bulling S;Schicker K;Zhang YW;Steinkellner T;Stockner T;Gruber CW;Boehm S;Freissmuth M;Rudnick G;Sitte HH;Sandtner W
通讯作者：
Sandtner W
影响因子：
14.8
作者：
Combs SA;Deluca SL;Deluca SH;Lemmon GH;Nannemann DP;Nguyen ED;Willis JR;Sheehan JH;Meiler J
通讯作者：
Meiler J
DOI：
10.1152/ajpgi.1998.275.3.g433
发表时间：
1998-09-01
影响因子：
4.5
作者：
Chen, JX;Pan, H;Gershon, MD
通讯作者：
Gershon, MD