Department of Pharmacology, University of the Basque Country (UPV/EHU), Leioa, Bizkaia, Spain.
Neuropharmacology. 2013 Feb;65:13-9. doi: 10.1016/j.neuropharm.2012.09.003. Epub 2012 Sep 11.
Evidence suggests that depression is associated with an increase in the high-affinity conformation of the α2-adrenoceptors in human brain. Such enhanced α2-adrenoceptor activity could explain the deficit in central noradrenergic transmission described in the aetiology of depression. Thus, administration of α2-adrenoceptor antagonists augments noradrenaline levels and provides an effective therapeutic approach for the treatment of depressive disorders. In previous studies, we have characterized three new synthesized guanidine and 2-aminoimidazoline aromatic derivatives (8b, 17b and 20b) as α2-adrenoceptor antagonists that are able to increase extracellular concentration of noradrenaline in rat brain. The purpose of the present study was to evaluate the in vivo antidepressant-like properties of these three new α2-adrenoceptor antagonists. For that aim, compounds were tested on the tail suspension test (TST) and forced swim test (FST), two classically widely-used behavioural paradigms for the evaluation of antidepressant-like activity. Compound 8b significantly reduced the immobility time at 10, 20 and 40 mg/kg doses in both TST and FST. Compound 17b reduced the immobility time at 40 mg/kg in both TST and FST. Compound 20b showed a significant decrease in the immobility time at 20 mg/kg in the TST. As drugs of reference, fluoxetine induced a significant antidepressant-like effect in both TST and FST, while mirtazapine induced a significant antidepressant-like effect only in the FST. Additionally, none of the tested compounds increased locomotor activity or displayed anxiolytic-like properties. These results suggest that these new synthesized α2-adrenoceptor antagonists may be useful as potential antidepressant drugs.
有证据表明，抑郁与人类大脑中高亲和力 α2-肾上腺素能受体的构象增加有关。这种增强的 α2-肾上腺素能受体活性可以解释抑郁发生机制中中枢去甲肾上腺素传递的缺陷。因此，α2-肾上腺素能受体拮抗剂的给药增加去甲肾上腺素水平，并为治疗抑郁障碍提供了一种有效的治疗方法。在以前的研究中，我们已经将三种新合成的胍和 2-氨基咪唑啉芳基衍生物（8b、17b 和 20b）表征为能够增加大鼠脑中去甲肾上腺素的细胞外浓度的 α2-肾上腺素能受体拮抗剂。本研究的目的是评估这三种新的 α2-肾上腺素能受体拮抗剂的体内抗抑郁样特性。为此，在悬尾试验（TST）和强迫游泳试验（FST）中测试了这些化合物，这两种行为范式常用于评估抗抑郁样活性。化合物 8b 在 TST 和 FST 中以 10、20 和 40mg/kg 剂量显著减少了不动时间。化合物 17b 在 TST 和 FST 中以 40mg/kg 剂量减少了不动时间。化合物 20b 在 TST 中以 20mg/kg 剂量显著减少了不动时间。作为参考药物，氟西汀在 TST 和 FST 中均表现出显著的抗抑郁样作用，而米氮平仅在 FST 中表现出显著的抗抑郁样作用。此外，测试的化合物均未增加运动活动或表现出抗焦虑样特性。这些结果表明，这些新合成的 α2-肾上腺素能受体拮抗剂可能作为潜在的抗抑郁药物有用。
