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

https://doi.org/10.1021/acs.jmedchem.3c00430.s004
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posted on 2023-07-07, 16:05 authored by Katarzyna Szczepańska, Tadeusz Karcz, Maria Dichiara, Szczepan Mogilski, Justyna Kalinowska-Tłuścik, Bogusław Pilarski, Arkadiusz Leniak, Wojciech Pietruś, Sabina Podlewska, Katarzyna Popiołek-Barczyk, Laura J. Humphrys, M. Carmen Ruiz-Cantero, David Reiner-Link, Luisa Leitzbach, Dorota Łażewska, Steffen Pockes, Michał Górka, Adam Zmysłowski, Thierry Calmels, Enrique J. Cobos, Agostino Marrazzo, Holger Stark, Andrzej J. Bojarski, Emanuele Amata, Katarzyna Kieć-Kononowicz

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.