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

• Published in: Journal of medicinal chemistry 2023-07, Vol.66 (14), p.9658-9683
• Main Authors: Szczepańska, Katarzyna, Karcz, Tadeusz, Dichiara, Maria, Mogilski, Szczepan, Kalinowska-Tłuścik, Justyna, Pilarski, Bogusław, Leniak, Arkadiusz, Pietruś, Wojciech, Podlewska, Sabina, Popiołek-Barczyk, Katarzyna, Humphrys, Laura J., Ruiz-Cantero, M. Carmen, Reiner-Link, David, Leitzbach, Luisa, Łażewska, Dorota, Pockes, Steffen, Górka, Michał, Zmysłowski, Adam, Calmels, Thierry, Cobos, Enrique J., Marrazzo, Agostino, Stark, Holger, Bojarski, Andrzej J., Amata, Emanuele, Kieć-Kononowicz, Katarzyna
• Format: Article
• Language: English
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.3c00430

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.