High-efficacy 5-HT1A Agonists for antidepressant treatment:: A renewed opportunity
High-efficacy 5-HT1A Agonists for antidepressant treatment:: A renewed opportunity
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DOI：
10.1021/jm070714l
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发表时间：
2007-10-04
影响因子：
7.3
通讯作者：
Vacher, Bernard
中科院分区：
文献类型：
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作者：
Maurel, Jean Louis;Autin, Jean-Marie;Vacher, Bernard
我们报道了新的5-HT1A受体激动剂的发现，并描述了导致抗抑郁候选药物9 （f15599）的过程。9对5-HT1A结合位点具有纳摩尔亲和力，并且对其他5-HT1受体亚型、5-HT2-7受体家族以及许多gpcr、转运体、离子通道和酶具有超过1000倍的选择性。在信号转导的细胞模型中，9激活h5-HT1A受体，其功效优于典型的5-HT1A激动剂(+/-)-8- oh - dpat和正在进行临床试验的比较物。大鼠急性口服后，9完全逆转强迫游泳试验中的不动，并产生5-HT1A受体激活的行为特征。然而，这些效应发生在广泛分离的剂量下，这表明9在不同的5-HT1A受体群体之间是有区别的。虽然这些观察结果的临床相关性尚不清楚，但这为抑郁症的治疗开辟了新的视角。
We report the discovery of novel 5-HT1A receptor agonists and describe the process that led to the antidepressant candidate 9 (F 15599). 9 has nanomolar affinity for 5-HT1A binding sites and is over 1000-fold selective with respect to the other 5-HT1 receptor subtypes, 5-HT2-7 receptor families, and also numerous GPCRs, transporters, ion channels, and enzymes. In a cellular model of signal transduction, 9 activates h5-HT1A receptors with an efficacy superior to that of the prototypical 5-HT1A agonist (+/-)-8-OH-DPAT and comparators undergoing clinical trials. After acute oral administration in rats, 9 totally reverses immobility in the forced swimming test and produces behaviors characteristic of 5-HT1A receptor activation. However, these effects occurred at widely separated doses, suggesting that 9 discriminates between distinct populations of 5-HT1A receptors. While the clinical relevance of these observations is still unknown, this opens new perspectives for the treatment of depressive disorders.