1区 · 医学
Article
作者: Leniak, Arkadiusz ; Ruiz-Cantero, M Carmen ; Podlewska, Sabina ; Pockes, Steffen ; Szczepańska, Katarzyna ; Humphrys, Laura J ; Calmels, Thierry ; Pilarski, Bogusław ; Bojarski, Andrzej J ; Stark, Holger ; Pietruś, Wojciech ; Łażewska, Dorota ; Kieć-Kononowicz, Katarzyna ; Amata, Emanuele ; Marrazzo, Agostino ; Popiołek-Barczyk, Katarzyna ; Dichiara, Maria ; Leitzbach, Luisa ; Górka, Michał ; Mogilski, Szczepan ; Cobos, Enrique J ; Reiner-Link, David ; Karcz, Tadeusz ; Kalinowska-Tłuścik, Justyna ; Zmysłowski, Adam
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.
