Discovery of 1-[2-(2,4-Dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): A Novel Multimodal Compound for the Treatment of Major Depressive Disorder
Discovery of 1-[2-(2,4-Dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): A Novel Multimodal Compound for the Treatment of Major Depressive Disorder
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DOI：
10.1021/jm101459g
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发表时间：
2011-05-12
影响因子：
7.3
通讯作者：
Stensbol, Tine Bryan
中科院分区：
文献类型：
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作者：
Bang-Andersen, Benny;Ruhland, Thomas;Stensbol, Tine Bryan
报道了一系列对5-羟色胺(5-HT3A)和5-羟色胺(5-HT1a)受体和5-羟色胺(5-HT)转运体(SERT)具有协同作用的新化合物的合成和构效关系。化合物5M(Lu AA21004)为先导化合物，对重组人5-HT1A(K-I=15 nM)、5-HT1B(K-I=33 nM)、5-HT3A(K-I=3.7 nM)、5-HT7(K-I=19 nM)和去甲肾上腺素能β(1)(K-I=46 nM)受体和SERT(K-I=1.6 nM)具有较高的亲和力。化合物5M对5-HT3A和5-HT7受体有拮抗作用，对5-HT1B受体有部分激动剂作用，对5-HT1a受体有激动剂作用，对SERT有较强的抑制作用。在清醒大鼠中，5M在急性和治疗3天后显著增加了脑细胞外5-羟色胺的水平。治疗3天(5或10 mg/kg)后，SERT占有率分别为43%和57%。这些特征表明，5M是一种新的多模式5-羟色胺能化合物，5M目前正处于治疗严重抑郁障碍的临床开发中。
The synthesis and structure-activity relationship of a novel series of compounds with combined effects on 5-HT3A and 5-HT1A receptors and on the serotonin (5-HT) transporter (SERT) are described. Compound 5m (Lu AA21004) was the lead compound, displaying high affinity for recombinant human 5-HT1A (K-i = 15 nM), 5-HT1B (K-i = 33 nM), 5-HT3A (K-i = 3.7 nM), 5-HT7 (K-i = 19 nM), and noradrenergic beta(1) (K-i = 46 nM) receptors, and SERT (K-i = 1.6 nM). Compound 5m displayed antagonistic properties at 5-HT3A and 5-HT7 receptors, partial agonist properties at 5-HT1B receptors, agonistic properties at 5-HT1A receptors, and potent inhibition of SERT. In conscious rats, 5m significantly increased extracellular 5-HT levels in the brain after acute and 3 days of treatment. Following the 3-day treatment (5 or 10 (mg/kg)/day) SERT occupancies were only 43% and 57%, respectively. These characteristics indicate that 5m is a novel multimodal serotonergic compound, and 5m is currently in clinical development for major depressive disorder.