School of Pharmacy, Pharmacology Unit, University of Camerino, Via Madonna delle Carceri 9, 62032 Camerino, Italy.
School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Via S. Agostino 1, 62032 Camerino, Italy.
ACS Chem Neurosci. 2020 Oct 7;11(19):3107-3116. doi: 10.1021/acschemneuro.0c00456. Epub 2020 Sep 21.
In this paper, the benzo-cracking approach was applied to the potent sigma1 (σ) receptor antagonist to afford the less conformationally constrained 1,3-dioxane derivatives and . To evaluate the effect of the increase in the distance between the two hydrophobic structural elements that flank the basic function, the and diastereomers of and were also prepared and studied. Compounds and showed affinity values at the σ receptor significantly higher than that of the lead compound . In particular, displayed unprecedented selectivity over the σ 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 , selected for an 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 σ receptor in the compulsive-like eating behavior and supported the σ receptor as a promising target for the management of eating disorders.
本文采用苯并裂解法，将强效σ1（σ）受体拮抗剂 转化为构象限制较小的 1,3-二氧戊环衍生物 和 。为了评估增加侧翼碱性官能团的两个疏水性结构元件之间的距离的效果，还制备并研究了 和 的非对映异构体 。化合物 和 在 σ 受体上的亲和力值明显高于先导化合物 。特别是 对 σ 受体、NMDA 受体的苯环己哌啶位点和阿片受体亚型以及多巴胺转运体表现出前所未有的选择性，同时还具有很高的选择性。对接结果支持了结构-活性关系研究。由于其有趣的生物学特征，在已验证的暴食行为的临床前模型中选择用于 研究的衍生物 ，仅在暴食大鼠中能够对抗美味食物的过度摄入，而在对照组中不影响美味食物的摄入，也不影响雌性大鼠的焦虑样和抑郁相关行为。这一结果强化了 σ 受体在强迫性进食行为中的作用，并支持 σ 受体作为治疗进食障碍的有前途的靶点。
