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 H-3/sigma-1receptorligands, we designed a series of compounds structurally based on highlyactive in vivo ligands previously studied and describedby 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 moietyin the structural core showed a significantly different affinity atsigma-1 receptors (& sigma;(1)Rs). Therefore, we first focusedon an in-depth analysis of the protonation states of piperazine andpiperidine derivatives in the studied compounds. In a series of 16new ligands, mainly based on the piperidine core, we selected threelead structures (3, 7, and 12) for further biological evaluation. Compound 12 showeda broad spectrum of analgesic activity in both nociceptive and neuropathicpain models based on the novel molecular mechanism.

Automated summary

In search of new dual-acting histamine H-3/sigma-1 receptor ligands, a series of compounds were designed based on previously studied highly active in vivo ligands. An in-depth analysis was conducted on the protonation states of piperazine and piperidine derivatives in the compounds, due to the significant difference in affinity at sigma-1 receptors observed in closely related compounds. Three lead structures (3, 7, and 12) were selected for further biological evaluation, and compound 12 showed a broad spectrum of analgesic activity based on a novel molecular mechanism in both nociceptive and neuropathic pain models.