Despite recent advances, current antidepressants have considerable limitations: late onset of action and the high profile of refractoriness. Biomedical research with natural products has gained growing interest in the last years, and had provide useful candidates for new antidepressants. Riparins are a group of natural alkamides obtained from Aniba riparia, which had marked neuroactive effects, mainly as antidepressant and antinociceptive agents. We made modifications of the basic structure of riparins, originating a synthetic alkamide, also known as riparin IV (RipIV). RipIV demonstrated a superior analgesic effect than its congeners and a marked antidepressant-like effect. However, the basic mechanism for the central effects of RipIV remains unknown. Here, we aimed to investigate the participation of monoaminergic neurotransmission targets in the antidepressant-like effects of RipIV. To do this, we applied a combined approach of experimental (classical pharmacology and neurochemistry) and computer-aided techniques. Our results demonstrated that RipIV presented antidepressant- and anxiolytic-like effects without modifying locomotion and motor coordination of mice. Also, RipIV increased brain monoamines and their metabolite levels. At the higher dose (100 mg/kg), RipIV increased serotonin concentrations in all studied brain areas, while at the lower one (50 mg/kg), it increased mainly dopamine and noradrenaline levels. When tested with selective receptor antagonists, RipIV antidepressant effect showed dependence of the activation of multiple targets, including D1 and D2 dopamine receptors, 5-HT2A/2, 5-HT3 receptors and α2 adrenergic receptors. Molecular docking demonstrated favorable binding conformation and affinity of RipIV to monoamine oxidase B (MAO-B), serotonin transporter (SERT), α1 receptor, D2 receptor, dopamine transporter (DAT) and at some extent GABA-A receptor. RipIV also presented a computationally predicted favorable pharmacokinetic profile. Therefore, this study demonstrated the involvement of monoaminergic targets in the mechanism of RipIV antidepressant-like action, and provide evidence of it as a promising new antidepressant.

中文翻译：

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单胺能靶点参与合成链烷酰胺肝素IV的抗抑郁和抗焦虑样作用：通过药理，神经化学和计算方法阐明进一步的机制。

尽管有最近的进展，但是目前的抗抑郁药具有相当大的局限性：起效较晚且难治性高。近年来，对天然产物进行生物医学研究的兴趣日益浓厚，并为新型抗抑郁药提供了有用的候选药物。Riparins是一组从河南阿尼巴（Aniba riparia）获得的天然烷酰胺，具有显着的神经活性作用，主要用作抗抑郁药和镇痛药。我们对riparins的基本结构进行了修改，源自合成的链烷酰胺，也称为riparin IV（RipIV）。RipIV的镇痛作用优于同类药物，并且具有明显的抗抑郁作用。但是，RipIV的中心作用的基本机制仍然是未知的。这里，我们旨在研究单胺能神经传递靶标参与RipIV的抗抑郁样作用。为此，我们采用了实验（经典药理学和神经化学）与计算机辅助技术相结合的方法。我们的结果表明，RipIV表现出抗抑郁和抗焦虑样作用，而不会改变小鼠的运动和运动协调性。同样，RipIV增加了脑单胺及其代谢产物的水平。在较高剂量（100 mg / kg）下，RipIV在所有研究的大脑区域均增加血清素浓度，而在较低剂量（50 mg / kg）下，其主要增加多巴胺和去甲肾上腺素的水平。当使用选择性受体拮抗剂进行测试时，RipIV的抗抑郁作用显示出对多个靶标（包括D1和D2多巴胺受体5-HT2A / 2，5-HT3受体和α2肾上腺素能受体。分子对接证明了RipIV与单胺氧化酶B（MAO-B），5-羟色胺转运蛋白（SERT），α1受体，D2受体，多巴胺转运蛋白（DAT）以及某种程度上的GABA-A受体具有良好的结合构象和亲和力。RipIV还显示了计算预测的有利药代动力学特征。因此，这项研究证明了单胺能靶点参与RipIV类抗抑郁药作用的机制，并提供了其作为有希望的新型抗抑郁药的证据。RipIV还显示了计算预测的有利药代动力学特征。因此，这项研究证明了单胺能靶点参与RipIV类抗抑郁药作用的机制，并提供了其作为有希望的新型抗抑郁药的证据。RipIV还显示了计算预测的有利药代动力学特征。因此，这项研究证明了单胺能靶点参与RipIV类抗抑郁药作用的机制，并提供了其作为有希望的新型抗抑郁药的证据。