The development of medications to treat cocaine use disorders has thus far defied success, leaving this patient population without pharmacotherapeutic options. As the dopamine transporter (DAT) plays a prominent role in the reinforcing effects of cocaine that can lead to addiction, atypical DAT inhibitors have been developed that prevent cocaine from binding to DAT, but they themselves are not cocaine-like. Herein, a series of novel DAT inhibitors were synthesized, and based on its pharmacological profile, the lead compound 10a was evaluated in phase I metabolic stability studies in mouse liver microsomes and compared to cocaine in locomotor activity and drug discrimination paradigms in mice. A molecular dynamic simulation study supported the hypothesis that atypical DAT inhibitors have similar binding poses at DAT in a conformation that differs from that of cocaine. Such differences may ultimately contribute to their unique behavioral profiles and potential for development as cocaine use disorder therapeutics.

中文翻译：

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一系列 3α-[双(4-氟苯基)甲氧基]托烷和 3α-[双(4-氟苯基)甲氨基]托烷作为新型非典型多巴胺转运蛋白 (DAT) 抑制剂治疗可卡因使用障碍的构效关系研究。

迄今为止，治疗可卡因使用障碍的药物开发尚未取得成功，使该患者群体没有药物治疗选择。由于多巴胺转运蛋白 (DAT) 在可导致成瘾的可卡因增强作用中发挥着重要作用，因此开发了非典型 DAT 抑制剂来阻止可卡因与 DAT 结合，但它们本身并不像可卡因。在此，合成了一系列新型 DAT 抑制剂，并根据其药理学特征，在小鼠肝微粒体的 I 期代谢稳定性研究中评估了先导化合物 10a，并在小鼠的运动活性和药物辨别范例中与可卡因进行了比较。一项分子动力学模拟研究支持了以下假设：非典型 DAT 抑制剂在 DAT 上具有相似的结合姿势，其构象与可卡因不同。这些差异可能最终有助于它们独特的行为特征和作为可卡因使用障碍疗法的开发潜力。