Dual Piperidine-Based Histamine H3 and Sigma-1 Receptor Ligands in the Treatment of Nociceptive and Neuropathic Pain
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ACS Publications
Date
2023-07-07Referencia bibliográfica
J. Med. Chem. 2023, XXXX, XXX, XXX-XXX[https://doi.org/10.1021/acs.jmedchem.3c00430]
Abstract
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.