Abstract
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.
Highlights
IntroductionSigma (σ) receptors are scarcely understood transmembrane proteins involved in a large number of cellular functions.[1]
Sigma (σ) receptors are scarcely understood transmembrane proteins involved in a large number of cellular functions.[1]Initially, they were classified as subtypes of the opioid receptor family, and subsequently, it was hypothesized that they corresponded to the phencyclidine (PCP) binding site of the ionotropic N-methyl-D-aspartate (NMDA) receptor
They were classified as subtypes of the opioid receptor family, and subsequently, it was hypothesized that they corresponded to the phencyclidine (PCP) binding site of the ionotropic N-methyl-D-aspartate (NMDA) receptor
Summary
Sigma (σ) receptors are scarcely understood transmembrane proteins involved in a large number of cellular functions.[1] They were classified as subtypes of the opioid receptor family, and subsequently, it was hypothesized that they corresponded to the phencyclidine (PCP) binding site of the ionotropic N-methyl-D-aspartate (NMDA) receptor. Membrane and play a role in the cellular stress response and homeostasis.[8,9] Their wide distribution in the nervous system and their involvement in several physiological and pathological conditions make σ1 receptors very promising targets for the management of numerous disorders. Compulsive fast overeating and strong craving, with a consequent withdrawal for hedonic food and impulsivity, are features correlated with binge eating behavior, to substance dependence.[21,22] In a pioneering study, the σ1 antagonist BD-1063 (Figure 1) was proven to reduce binge-like eating and to block compulsive eating in Received: July 20, 2020 Accepted: September 4, 2020 Published: September 4, 2020
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