10日，记者从合肥综合性国家科学中心大健康研究院获悉，该院曹灿、王春玉团队联合中国科学技术大 学薛天团队、天津医科大学陈贺团队等，提出一种快速抗抑郁新策略，并设计出候选化合物 TMU4142，该化合物在动物实验中呈现显著的快速抗抑郁效果，且无明显副作用，为研发新一代快速 抗抑郁药物提供了新思路。相关成果日前在线发表于国际期刊《细胞》。 在研发过程中，研究团队注意到前人研究中报道不同脑区血清素1A受体，在下游信号传递中会"偏 好"结合不同G蛋白类型来发挥功能，中缝背核受体主要与Gi3蛋白结合，而海马体及皮质区的受体则主 要结合GoA蛋白。团队据此提出新策略：设计一种"偏好"激活GoA蛋白的化合物，在维持对GoA蛋白激 活能力的同时，弱化其对Gi3蛋白的激活，从而精准调控有益通路、规避延迟起效的有害效应。 研究团队以具有部分GoA蛋白激活特性的老药Pindolol为参考分子骨架，优化并合成了新候选化合物 TMU4142。在新奇食物抑制实验中，TMU4142注射1小时即可改善小鼠抑郁状态。神经化学检测进一步 证实，该化合物在治疗剂量下不会引发中缝背核区域自身受体介导负反馈作用。 曹灿表示，团队下一步将持续优化化合物 ...

Core Viewpoint - The article discusses the rising prevalence of depression and introduces a new rapid antidepressant strategy based on selective activation of the 5-HT 1A receptor, which addresses the slow onset of traditional SSRIs [3][6][12]. Group 1: Background on Depression and SSRIs - Depression has become a leading cause of disability globally, surpassing cardiovascular diseases and cancer [3]. - The monoamine hypothesis, proposed in the 1950s, links depression to a deficiency of monoamine neurotransmitters, leading to the development of various antidepressants [3]. - SSRIs are the latest generation of antidepressants that increase serotonin levels in the brain but often take weeks to show effects and can have side effects [3][6]. Group 2: New Research Findings - A research team published a study in the journal Cell, proposing a pathway-selective 5-HT 1A receptor agonist as a rapid antidepressant strategy [5]. - The study introduces TMU4142, a candidate agonist that shows significant rapid antidepressant effects in mouse models [6][8]. - The research characterizes the G i/o signaling features of the 5-HT 1A receptor and identifies the structural interactions with various agonists and G i/o family proteins [8][10]. Group 3: Mechanism and Implications - TMU4142 selectively activates G oA while minimizing G i3 activation, leading to rapid antidepressant effects without activating the 5-HT 1A receptor in the dorsal raphe nucleus [10][12]. - The findings suggest that distinguishing between downstream G i/o signaling pathways of heteroreceptors and autoreceptors could be a promising strategy for developing fast-acting antidepressants [12].