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.

为开发新型双靶点组胺H3/σ1受体配体（histamine H3/sigma-1 receptor ligands），我们基于本团队此前研究并报道的高活性体内配体，设计了一系列结构相关化合物。但我们注意到，在前期的化合物系列中，一对仅在核心结构的哌嗪（piperazine）/哌啶（piperidine）基团上存在差异的结构高度相似化合物KSK67与KSK68，在σ1受体（sigma-1 receptors, σ1Rs）上展现出显著不同的结合亲和力。因此，我们首先针对所研究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（piperidine）为母核的新型配体中，我们筛选出3个先导化合物用于后续生物学评价。化合物12基于全新的分子作用机制，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。