Journal
ACS CHEMICAL NEUROSCIENCE
Volume 11, Issue 19, Pages 3107-3116Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.0c00456
Keywords
Selective sigma1 ligands; binge eating episode; highly palatable food; open field test; forced swimming test
Funding
- University of Camerino (Fondo di Ateneo per la Ricerca 2018)
- University of Camerino (Fondo di Ateneo per la Ricerca 2019)
- Italian Ministry of Education, University and Research [PRIN2015KP7T2Y]
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In this paper, the benzo-cracking approach was applied to the potent sigma1 (sigma(1)) 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 sigma(1) receptor significantly higher than that of the lead compound 1. In particular, 3 displayed unprecedented selectivity over the sigma(2) 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 s1 receptor in the compulsive-like eating behavior and supported the s1 receptor as a promising target for the management of eating disorders.
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