Dual Piperidine-Based Histamine H₃ and Sigma‑1 Receptor Ligands in the Treatment of Nociceptive and Neuropathic Pain

In search of new dual-acting histamine H3/sigma-1 receptor ligands, we designed a series of compounds structurally based on highly active in vivo ligands previously studied and described by our team. However, we kept in mind that within the previous series, a pair of closely related compounds, KSK67 and KSK68, differing only in the piperazine/piperidine moiety in the structural core showed a significantly different affinity at sigma-1 receptors (σ1Rs). Therefore, we first focused on an in-depth analysis of the protonation states of piperazine and piperidine derivatives in the studied compounds. In a series of 16 new ligands, mainly based on the piperidine core, we selected three lead structures (3, 7, and 12) for further biological evaluation. Compound 12 showed a broad spectrum of analgesic activity in both nociceptive and neuropathic pain models based on the novel molecular mechanism.为研发新型双靶点组胺H3/σ1受体（sigma-1 receptor）配体，本研究基于课题组此前已研究并报道的高活性体内配体，设计了一系列结构相关的化合物。但我们注意到，在前期系列化合物中，一对结构高度相似的化合物KSK67与KSK68仅在核心结构的哌嗪/哌啶片段上存在差异，二者在σ1受体上的结合亲和力却存在显著差异。因此，本研究首先针对受试化合物中哌嗪与哌啶衍生物的质子化状态展开深入分析。在16个主要以哌啶为核心结构的新型配体中，我们筛选出3个先导化合物（编号3、7、12）用于后续生物学评价。化合物12基于全新的分子机制，在伤害感受性疼痛与神经病理性疼痛模型中均展现出广谱的镇痛活性。