In this paper, the benzo-cracking approach was applied to the potent sigma1 (σ₁) receptor antagonist 1 to afford the less conformationally constrained 1,3-dioxane derivatives 2 and 3. To evaluate the effect of the increase in the distance between the two hydrophobic structural elements that flank the basic function, the cis and trans diastereomers of 4 and 5 were also prepared and studied. Compounds 2 and 3 showed affinity values at the σ₁ receptor significantly higher than that of the lead compound 1. In particular, 3 displayed unprecedented selectivity over the σ₂ receptor, the phencyclidine site of the NMDA receptor, and opioid receptor subtypes, as well as over the dopamine transporter. Docking results supported the structure–activity relationship studies. Due to its interesting biological profile, derivative 3, selected for an in vivo study in a validated preclinical model of binge eating, was able to counteract the overeating of palatable food only in binging rats, without affecting palatable food intake in the control group and anxiety-like and depression-related behaviors in female rats. This result strengthened the involvement of the σ₁ receptor in the compulsive-like eating behavior and supported the σ₁ receptor as a promising target for the management of eating disorders.

中文翻译：

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新型的高效和选择性的Sigma1受体拮抗剂有效地阻断了雌性大鼠的暴食饮食情节。

在本文中，所述苯并裂化方法被施加到有效的sigma1（σ ₁）受体拮抗剂1，得到以下构象受限1,3-二恶烷衍生物2和3。为了评估增加基本功能侧翼的两个疏水结构元件之间距离的影响，还制备并研究了4和5的顺式和反式非对映异构体。化合物2和3个在σ表明亲和力值₁受体比铅化合物的显著更高1。尤其是，3显示了前所未有的选择性比σ ₂受体，NMDA受体的苯环利定部位，和阿片样物质受体亚型，以及在多巴胺转运蛋白。对接结果支持结构-活性关系研究。由于其有趣的生物学特性，在经过验证的暴饮暴食的临床前模型中选择了用于体内研究的衍生物3，仅在暴饮暴食的老鼠中就可以抵消可口食物的暴饮暴食，而不会影响对照组的可口食物摄入量和焦虑症雌性大鼠的抑郁样行为和抑郁相关行为。这一结果加强了σ参与₁受体在强迫般的饮食行为和支持σ ₁ 受体作为饮食失调的有希望的靶标。