The design and synthesis of a series of piperidine and piperazine-based derivatives as selective sigma receptor (SR) ligands associated with analgesic activity, are the focus of this work. In this study, affinities at S1R and S2R were measured, and molecular modeling studies were performed to investigate the binding pose features. The most promising compounds were subjected to in vitro toxicity testing and subsequently screened for in vivo analgesic properties. Compounds 12a (AD353) and 12c (AD408) exhibited negligible in vitro cellular toxicity and high potency both in a model of capsaicin-induced allodynia and in PGE2-induced mechanical hyperalgesia. Functional activity experiments showed that S1R antagonism is needed for the effects of these compounds, since the effect was reversed by PRE-084 or absent in KO mice. In addition, 12a exhibited a favorable pharmacokinetic profile, confirming its therapeutic value in treating allodynic conditions. Moreover, a computational model was developed in order to help the understanding about the mechanism of action of most active compounds.

中文翻译：

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具有抗同种异体疼痛活性的选择性 sigma-1 受体配体的开发：专注于哌啶和哌嗪支架


设计和合成一系列哌啶和基于哌嗪的衍生物作为与镇痛活性相关的选择性 σ 受体 （SR） 配体，是这项工作的重点。在这项研究中，测量了 S1R 和 S2R 的亲和力，并进行了分子建模研究以研究结合姿势特征。最有前途的化合物进行了体外毒性测试，随后筛选了体内镇痛特性。化合物 12a （AD353） 和 12c （AD408） 在辣椒素诱导的异常性疼痛和 PGE2 诱导的机械痛觉过敏模型中表现出可忽略不计的体外细胞毒性和高效性。功能活性实验表明，这些化合物的作用需要 S1R 拮抗作用，因为该作用被 PRE-084 逆转或在 KO 小鼠中不存在。此外，12a 表现出良好的药代动力学特征，证实了其在治疗异常性疼痛方面的治疗价值。此外，还开发了一种计算模型，以帮助理解大多数活性化合物的作用机制。