School of Pharmacy, Medicinal Chemistry Unit , University of Camerino , Via S. Agostino 1 , 62032 Camerino , Italy.
School of Pharmacy, Pharmacology Unit , University of Camerino , Via Madonna delle Carceri 9 , 62032 Camerino , Italy.
ACS Chem Neurosci. 2019 Aug 21;10(8):3391-3397. doi: 10.1021/acschemneuro.9b00261. Epub 2019 Jul 23.
The enantiomers of the potent σ receptor antagonist (±)- were synthesized and evaluated for their affinity at σ, σ receptors and dopamine transporter (DAT). Analogously to (±)-, both of the enantiomers showed very high affinity for the σ receptor and unprecedented selectivity over both the σ receptor and DAT. The lack of enantioselectivity between ()- and (-)- 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 receptor. In in vivo studies in a female rat model of binge eating, (±)- 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 receptor in bingeing-related eating disorders.
强效 σ 受体拮抗剂（±）-对映异构体的合成及其与 σ、σ 受体和多巴胺转运体（DAT）的亲和力进行了评估。与（±）-类似，两种对映异构体对 σ 受体均表现出极高的亲和力，并且对 σ 受体和 DAT 具有前所未有的选择性。（）-和（-）之间没有对映选择性表明，苯并噻吩并色烯核 2 位的手性中心在与任何研究靶标相互作用时不起关键作用。对接研究证实，对映异构体的构型仅对与 σ 受体的分子相互作用产生微小影响。在女性大鼠暴食模型的体内研究中，（±）-剂量依赖性地降低了由间歇性食物限制和应激引起的暴食发作，证实并加强了 σ 受体在与暴食相关的进食障碍中的重要作用。
