Neuroscience Drug Discovery Denmark, H. Lundbeck A/S , 9 Ottiliavej, DK-2500 Copenhagen-Valby, Denmark.
J Med Chem. 2011 May 12;54(9):3206-21. doi: 10.1021/jm101459g. Epub 2011 Apr 12.
The synthesis and structure-activity relationship of a novel series of compounds with combined effects on 5-HT(3A) and 5-HT(1A) 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-HT(1A) (K(i) = 15 nM), 5-HT(1B) (K(i) = 33 nM), 5-HT(3A) (K(i) = 3.7 nM), 5-HT(7) (K(i) = 19 nM), and noradrenergic β(1) (K(i) = 46 nM) receptors, and SERT (K(i) = 1.6 nM). Compound 5m displayed antagonistic properties at 5-HT(3A) and 5-HT(7) receptors, partial agonist properties at 5-HT(1B) receptors, agonistic properties at 5-HT(1A) 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.
描述了一系列具有 5-HT(3A) 和 5-HT(1A) 受体以及血清素 (5-HT) 转运体 (SERT) 双重作用的新型化合物的合成和构效关系。化合物 5m (Lu AA21004) 是先导化合物，对重组人 5-HT(1A) (K(i) = 15 nM)、5-HT(1B) (K(i) = 33 nM)、5-HT(3A) (K(i) = 3.7 nM)、5-HT(7) (K(i) = 19 nM) 和去甲肾上腺素能β(1) (K(i) = 46 nM) 受体以及 SERT (K(i) = 1.6 nM) 具有高亲和力。化合物 5m 在 5-HT(3A) 和 5-HT(7) 受体上表现出拮抗特性，在 5-HT(1B) 受体上表现出部分激动特性，在 5-HT(1A) 受体上表现出激动特性，并能有效抑制 SERT。在清醒大鼠中，5m 在急性和 3 天治疗后显著增加大脑中的细胞外 5-HT 水平。在 3 天治疗后（5 或 10 (mg/kg)/天），SERT 占有率分别为 43%和 57%。这些特征表明 5m 是一种新型的多模态血清素化合物，目前正在开发用于治疗重度抑郁症。
