Structural and Molecular Insight into Piperazine and Piperidine Derivatives as Histamine H(3) and Sigma-1 Receptor Antagonists with Promising Antinociceptive Properties

[Image: see text] In an attempt to extend recent studies showing that some clinically evaluated histamine H(3) receptor (H(3)R) antagonists possess nanomolar affinity at sigma-1 receptors (σ(1)R), we selected 20 representative structures among our previously reported H(3)R 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 σ(1)R than σ(2)R with the highest binding preference to σ(1)R 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 H(3)/σ(1) receptor activity as can be seen by comparing the data for compounds 4 and 5 (hH(3)R K(i) = 3.17 and 7.70 nM, σ(1)R K(i) = 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 H(3) and σ(1) 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 σ(1) or H(3)R 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.