TY - JOUR
T1 - Novel highly potent and selective sigma1 receptor antagonists effectively block the binge eating episode in female rats
AU - Del Bello, Fabio
AU - Quaglia, Wilma
AU - Cifani, Carlo
AU - Micioni Di Bonaventura, Emanuela
AU - Botticelli, Luca
AU - Giorgioni, Gianfabio
AU - Pavletic, Pegi
AU - Piergentili, Alessandro
AU - Bonifazi, Alessandro
AU - Schepmann, Dirk
AU - Vistoli, Giulio
AU - Micioni Di Bonaventura, Maria Vittoria
N1 - Publisher Copyright:
© 2020 American Chemical Society.
PY - 2020/10/7
Y1 - 2020/10/7
N2 - 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.
AB - 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.
KW - Binge eating episode
KW - Forced swimming test
KW - Highly palatable food
KW - Open field test
KW - Selective sigma1 ligands
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U2 - 10.1021/acschemneuro.0c00456
DO - 10.1021/acschemneuro.0c00456
M3 - Article
C2 - 32886484
AN - SCOPUS:85092681371
SN - 1948-7193
VL - 11
SP - 3107
EP - 3116
JO - ACS chemical neuroscience
JF - ACS chemical neuroscience
IS - 19
ER -