N-Desalkylquetiapine, a potent norepinephrine reuptake inhibitor and partial 5-HT1A agonist, as a putative mediator of quetiapine's antidepressant activity
N-Desalkylquetiapine, a potent norepinephrine reuptake inhibitor and partial 5-HT1A agonist, as a putative mediator of quetiapine's antidepressant activity
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DOI：
10.1038/sj.npp.1301646
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发表时间：
2008-09-01
影响因子：
7.6
通讯作者：
Roth, Bryan L.
中科院分区：
文献类型：
--
作者：
Jensen, Niels H.;Rodriguiz, Ramona M.;Roth, Bryan L.
奎替鲁是一种非典型的抗精神病药物，也是美国FDA批准用于治疗双相抑郁症，尽管机制未知。为了发现这一明显独特作用的潜在机制，我们筛选了喹替鲁、其代谢物N-脱烷基喹替鲁和二苯并[B，f][1，4]硫氮杂卓-11（10-H）-酮（DBTO），以对抗大量G蛋白偶联受体、离子通道和神经递质转运蛋白。DBTO对所有测试的分子靶标均无活性。N-去烷基喹替卡松对组胺H-1受体具有高亲和力（3.4 nM），对去甲肾上腺素再摄取转运蛋白（NET）、5-羟色胺5-HT 1A、5-HT 1 E、5-HT 2A、5-HT 2B、5-HT 7受体、α（1B）-肾上腺素能受体以及M-1、M-3和M-5毒蕈碱受体具有中等亲和力（10 - 100 nM）。该化合物对5-HT 1D、5-HT 2C、5-HT 3、5-HT 5、5-HT 6、α（1A）、α（2A）、α（2B）、α（2C）、H-2、M-2、M-4和多巴胺D-1、D-2、D-3和D-4受体的亲和力较低（100-1000 nM）。N-去烷基喹替鲁肽有效抑制人NE转运蛋白，Ki为12 nM，比喹替鲁肽本身有效约100倍。N-去烷基喹替鲁胺对5-HT 1A受体的效力和有效性也是喹替鲁胺的10倍。N-去烷基喹替麦酮是5-HT 2A、5-HT 2B、5-HT 2C、α（1A）、α（1D）、α（2A）、α（2C）、H-1、M-1、M-3和M-5受体的拮抗剂。在小鼠悬尾试验中，N-去烷基喹替麦酮在低至0.1 mg/kg的剂量下在VMAT 2杂合子小鼠中显示出强效抗抑郁样活性。这些数据强烈表明，喹替鲁胺的抗抑郁活性至少部分是由其代谢物N-脱烷基喹替鲁胺通过NET抑制和部分5-HT 1A激动介导的。这种代谢产物的副作用奎替鲁肽可能的贡献进行了讨论。
Quetiapine is an atypical antipsychotic drug that is also US FDA approved for treating bipolar depression, albeit by an unknown mechanism. To discover the potential mechanism for this apparently unique action, we screened quetiapine, its metabolite N-Desalkylquetiapine, and dibenzo[b,f][ 1,4] thiazepine-11(10-H)-one (DBTO) against a large panel of G-protein - coupled receptors, ion channels, and neurotransmitter transporters. DBTO was inactive at all tested molecular targets. N-Desalkylquetiapine had a high affinity (3.4 nM) for the histamine H-1 receptor and moderate affinities (10 - 100 nM) for the norepinephrine reuptake transporter (NET), the serotonin 5-HT1A, 5-HT1E, 5-HT2A, 5-HT2B, 5-HT7 receptors, the alpha(1B)-adrenergic receptor, and the M-1, M-3, and M-5 muscarinic receptors. The compound had low affinities (100-1000 nM) for the 5-HT1D, 5-HT2C, 5-HT3, 5-HT5, 5-HT6, alpha(1A), alpha(2A), alpha(2B), alpha(2C), H-2, M-2, M-4, and dopamine D-1, D-2, D-3, and D-4 receptors. N-Desalkylquetiapine potently inhibited human NE transporter with a K-i of 12 nM, about 100-fold more potent than quetiapine itself. N-Desalkylquetiapine was also 10-fold more potent and more efficacious than quetiapine at the 5-HT1A receptor. N-Desalkylquetiapine was an antagonist at 5-HT2A, 5-HT2B, 5-HT2C, alpha(1A), alpha(1D), alpha(2A), alpha(2C), H-1, M-1, M-3, and M-5 receptors. In the mouse tail suspension test, N-Desalkylquetiapine displayed potent antidepressant-like activity in VMAT2 heterozygous mice at doses as low as 0.1 mg/kg. These data strongly suggest that the antidepressant activity of quetiapine is mediated, at least in part, by its metabolite N-Desalkylquetiapine through NET inhibition and partial 5-HT1A agonism. Possible contributions of this metabolite to the side effects of quetiapine are discussed.