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Dual Piperidine-Based Histamine H 3 and Sigma-1 Receptor Ligands in the Treatment of Nociceptive and Neuropathic Pain

2023; American Chemical Society; Volume: 66; Issue: 14 Linguagem: Inglês

10.1021/acs.jmedchem.3c00430

1520-4804

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,

Phenothiazines and Benzothiazines Synthesis and Activities

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.