Structural and Molecular Insight into Piperazine and Piperidine Derivatives as Histamine H3 and Sigma‑1 Receptor Antagonists with Promising Antinociceptive Properties Szczepanska, Katarzyna Ruiz Cantero, María del Carmen Cobos del Moral, Enrique José Histamine H3 receptor Sigma-1 receptor Sigma-2 receptor Piperazine derivatives Piperidine derivatives Dual targeting compounds Molecular docking Dynamics Functional characterization We are pleased to acknowledge the generous support of the National Science Center, Poland, granted based on decision No. 2020/36/C/NZ7/00284. Support by ERNEST COST Action 18133 is also acknowledged. K. Szczepan ' ska is supported by the Foundation of Polish Science within the START scholarship. Financial support by the graduate school "Receptor Dynamics" of the Elite Network of Bavaria (ENB) is gratefully acknowledged (N. Rosier, S. Pockes). M. C. Ruiz Cantero was supported by the Training University Lecturers program (FPU) of the Spanish Ministry of Economy and Competitiveness (MINECO). We also acknowledge funding from the Spanish State Research Agency (10.13039/501100011033) under the auspices of MINECO (grant number PID2019-108691RB-I00 to E. J. Cobos) as well as from the University of Catania, PIA.CE.RI. 2020-2022 Linea di intervento 3 Starting Grant project CARETO (grant 57722172136 to E. Amata). In an attempt to extend recent studies showing that some clinically evaluated histamine H3 receptor (H3R) antagonists possess nanomolar affinity at sigma-1 receptors (σ1R), we selected 20 representative structures among our previously reported H3R ligands to investigate their affinity at σRs. Most of the tested compounds interact with both sigma receptors to different degrees. However, only six of them showed higher affinity toward σ1R than σ2R with the highest binding preference to σ1R for compounds 5, 11, and 12. Moreover, all these ligands share a common structural feature: the piperidine moiety as the fundamental part of the molecule. It is most likely a critical structural element for dual H3/σ1 receptor activity as can be seen by comparing the data for compounds 4 and 5 (hH3R Ki = 3.17 and 7.70 nM, σ1R Ki = 1531 and 3.64 nM, respectively), where piperidine is replaced by piperazine. We identified the putative protein−ligand interactions responsible for their high affinity using molecular modeling techniques and selected compounds 5 and 11 as lead structures for further evaluation. Interestingly, both ligands turned out to be high-affinity histamine H3 and σ1 receptor antagonists with negligible affinity at the other histamine receptor subtypes and promising antinociceptive activity in vivo. Considering that many literature data clearly indicate high preclinical efficacy of individual selective σ1 or H3R ligands in various pain models, our research might be a breakthrough in the search for novel, dual-acting compounds that can improve existing pain therapies. Determining whether such ligands are more effective than single-selective drugs will be the subject of our future studies. 2022-01-26T08:02:25Z 2022-01-26T08:02:25Z 2021-12-15 info:eu-repo/semantics/article ACS Chem. Neurosci. 2022, 13, 1, 1–15. [https://doi.org/10.1021/acschemneuro.1c00435] http://hdl.handle.net/10481/72485 10.1021/acschemneuro.1c00435 eng http://creativecommons.org/licenses/by/3.0/es/ info:eu-repo/semantics/openAccess Atribución 3.0 España American Chemical Society