The enantiomers of the potent σ1 receptor antagonist (±)-1 were synthesized and evaluated for their affinity at σ1, σ2 receptors and dopamine transporter (DAT). Analogously to (±)-1, both of the enantiomers showed very high affinity for the σ1 receptor and unprecedented selectivity over both the σ2 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 σ1 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 σ1 receptor in bingeing-related eating disorders.
Investigation of the Role of Chirality in the Interaction with σ Receptors and Effect on Binge Eating Episode of a Potent σ1 Antagonist Analogue of Spipethiane / F. Del Bello, M.V. Micioni Di Bonaventura, A. Bonifazi, B. Wunsch, D. Schepmann, J.B. Giancola, E.M. Di Bonaventura, G. Vistoli, G. Giorgioni, W. Quaglia, A. Piergentili, C. Cifani. - In: ACS CHEMICAL NEUROSCIENCE. - ISSN 1948-7193. - 10:8(2019 Aug 21), pp. 3391-3397. [10.1021/acschemneuro.9b00261]
Investigation of the Role of Chirality in the Interaction with σ Receptors and Effect on Binge Eating Episode of a Potent σ1 Antagonist Analogue of Spipethiane
G. Vistoli;
2019
Abstract
The enantiomers of the potent σ1 receptor antagonist (±)-1 were synthesized and evaluated for their affinity at σ1, σ2 receptors and dopamine transporter (DAT). Analogously to (±)-1, both of the enantiomers showed very high affinity for the σ1 receptor and unprecedented selectivity over both the σ2 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 σ1 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 σ1 receptor in bingeing-related eating disorders.File | Dimensione | Formato | |
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