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Dual- and triple-acting agents for treating core and co-morbid symptoms of major depression: novel concepts, new drugs.
Neurotherapeutics ( IF 5.7 ) Pub Date : 2008 , DOI: 10.1016/j.nurt.2008.10.039
Mark J Millan 1
Affiliation  

The past decade of efforts to find improved treatment for major depression has been dominated by genome-driven programs of rational drug discovery directed toward highly selective ligands for nonmonoaminergic agents. Selective drugs may prove beneficial for specific symptoms, for certain patient subpopulations, or both. However, network analyses of the brain and its dysfunction suggest that agents with multiple and complementary modes of action are more likely to show broad-based efficacy against core and comorbid symptoms of depression. Strategies for improved multitarget exploitation of monoaminergic mechanisms include triple inhibitors of dopamine, serotonin (5-HT) and noradrenaline reuptake, and drugs interfering with feedback actions of monoamines at inhibitory 5-HT1A, 5-HT1B and possibly 5-HT5A and 5-HT7 receptors. Specific subsets of postsynaptic 5-HT receptors mediating antidepressant actions are under study (e.g., 5-HT4 and 5-HT6). Association of a clinically characterized antidepressant mechanism with a nonmonoaminergic component of activity is an attractive strategy. For example, agomelatine (a melatonin agonist/5-HT2C antagonist) has clinically proven activity in major depression. Dual neurokinin1 antagonists/5-HT reuptake inhibitors (SRIs) and melanocortin4 antagonists/SRIs should display advantages over their selective counterparts, and histamine H3 antagonists/SRIs, GABAB antagonists/SRIs, glutamatergic/SRIs, and cholinergic agents/SRIs may counter the compromised cognitive function of depression. Finally, drugs that suppress 5-HT reuptake and blunt hypothalamo-pituitary-adrenocorticotrophic axis overdrive, or that act at intracellular proteins such as GSK-3β, may abrogate the negative effects of chronic stress on mood and neuronal integrity. This review discusses the discovery and development of dual- and triple-acting antidepressants, focusing on novel concepts and new drugs disclosed over the last 2 to 3 years.

中文翻译:

用于治疗重度抑郁症核心和共病症状的双效和三效药物:新概念、新药。

在过去十年中,寻找改善重度抑郁症治疗方法的努力主要是由基因组驱动的合理药物发现计划主导的,这些计划针对非单胺能药物的高选择性配体。选择性药物可能证明对特定症状、某些患者亚群或两者都有益。然而,对大脑及其功能障碍的网络分析表明,具有多种互补作用模式的药物更有可能对抑郁症的核心和共病症状表现出广泛的疗效。改进单胺能机制的多靶点开发的策略包括多巴胺、血清素 (5-HT) 和去甲肾上腺素再摄取的三重抑制剂,以及干扰单胺在抑制性 5-HT 1A、5-HT 1B处的反馈作用的药物可能还有 5-HT 5A和 5-HT 7受体。正在研究介导抗抑郁作用的突触后 5-HT 受体的特定子集(例如,5-HT 4和 5-HT 6)。将具有临床特征的抗抑郁机制与非单胺能活性成分联系起来是一种有吸引力的策略。例如,阿戈美拉汀(一种褪黑激素激动剂/5-HT 2C拮抗剂)在重度抑郁症中具有临床证明的活性。双神经激肽1拮抗剂 / 5-HT 再摄取抑制剂 (SRI) 和黑皮质素4拮抗剂 / SRI 应显示优于其选择性对应物的优势,组胺 H 3拮抗剂 / SRI、GABA B拮抗剂 / SRI、谷氨酸能 / SRI 和胆碱能药物 / SRI 可能对抗抑郁症受损的认知功能。最后,抑制 5-HT 再摄取和钝性下丘脑 - 垂体 - 促肾上腺皮质激素轴过度驱动的药物,或作用于细胞内蛋白质(如 GSK-3β)的药物可能会消除慢性压力对情绪和神经元完整性的负面影响。本综述讨论了双效和三效抗抑郁药的发现和开发,重点关注过去 2 至 3 年中披露的新概念和新药。
更新日期:2020-09-23
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