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In this paper, the benzo-cracking approach was applied to the potent sigma1 (σ 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 σ 1 receptor significantly higher than that of the lead compound 1 . In particular, 3 displayed unprecedented selectivity over the σ 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 σ 1 receptor in the compulsive-like eating behavior and supported the σ 1 receptor as a promising target for the management of eating disorders.

The enantiomers of the potent σ 1 receptor antagonist (±)- 1 were synthesized and evaluated for their affinity at σ 1 , σ 2 receptors and dopamine transporter (DAT). Analogously to (±)- 1 , both of the enantiomers showed very high affinity for the σ 1 receptor and unprecedented selectivity over both the σ 2 receptor and DAT. The lack of enantioselectivity between ( + )- 1 and (-)- 1 indicated that the center of chirality in the 2-position of the benzothiochromane nucleus does not play a crucial role in the interaction with any of the studied targets. Docking studies confirmed that the configuration of the enantiomers has only marginal effects on the molecular interactions with the σ 1 receptor. In in vivo studies in a female rat model of binge eating, (±)- 1 dose-dependently decreased the binge eating episode elicited by a history of intermittent food restriction and stress, confirming and strengthening the important role played by the σ 1 receptor in bingeing-related eating disorders.