Novel Highly Potent and Selective Sigma1 Receptor Antagonists Effectively Block the Binge Eating Episode in Female Rats.
Novel Highly Potent and Selective Sigma1 Receptor Antagonists Effectively Block the Binge Eating Episode in Female Rats.
复制标题
DOI：
10.1021/acschemneuro.0c00456
复制
发表时间：
2020-10-07
影响因子：
5
通讯作者：
Micioni Di Bonaventura MV
中科院分区：
文献类型：
--
作者：
Cifani C;Micioni Di Bonaventura E;Botticelli L;Del Bello F;Giorgioni G;Pavletić P;Piergentili A;Quaglia W;Bonifazi A;Schepmann D;Wünsch B;Vistoli G;Micioni Di Bonaventura MV
在本文中，苯并裂解方法应用于有效的 sigma1 (σ1) 受体拮抗剂 1，以提供构象限制较少的 1,3-二恶烷衍生物 2 和 3。为了评估基本功能侧翼的两个疏水结构元件之间距离增加的影响，还制备并研究了 4 和 5 的顺式和反式非对映体。化合物 2 和 3 对 σ1 受体的亲和力值显着高于先导化合物 1。特别是，化合物 3 对 σ2 受体、NMDA 受体的苯环己哌啶位点、阿片受体亚型以及多巴胺转运蛋白表现出前所未有的选择性。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，衍生物 3 被选用于经过验证的暴食临床前模型的体内研究，仅能够抵消暴饮暴食大鼠的可口食物暴饮暴食，而不影响对照组的可口食物摄入以及雌性大鼠的焦虑样和抑郁相关行为。这一结果加强了 σ1 受体在强迫性饮食行为中的参与，并支持 σ1 受体作为饮食失调管理的有希望的靶点。
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.
登录
查看更多内容
影响因子：
2.9
作者：
Cifani, Carlo;Di B, Maria Vittoria Micioni;Massi, Maurizio
通讯作者：
Massi, Maurizio
DOI：
10.1073/pnas.93.15.8072
发表时间：
1996-07-23
影响因子：
11.1
作者：
Hanner, M;Moebius, FF;Glossmann, H
通讯作者：
Glossmann, H
影响因子：
3.4
作者：
Di Bonaventura, Maria Vittoria Micioni;Ubaldi, Massimo;Cifani, Carlo
通讯作者：
Cifani, Carlo
影响因子：
7.3
作者：
Bonifazi, Alessandro;Del Bello, Fabio;Quaglia, Wilma
通讯作者：
Quaglia, Wilma
DOI：
10.1007/978-3-319-50174-1_11
发表时间：
2017-01-01
期刊：
SIGMA RECEPTORS: THEIR ROLE IN DISEASE AND AS THERAPEUTIC TARGETS
影响因子：
--
作者：
Albayrak, Yakup;Hashimoto, Kenji
通讯作者：
Hashimoto, Kenji