Structural and Molecular Insight into Piperazine and Piperidine Derivatives as Histamine H3 and Sigma-1 Receptor Antagonists with Promising Antinociceptive Properties

In an attempt to extend recent studies showing that some clinically evaluated histamine H-3 receptor (H3R) antagonists possess nanomolar affinity at sigma-1 receptors (sigma R-1), we selected 20 representative structures among our previously reported H3R ligands to investigate their affinity at sigma Rs. Most of the tested compounds interact with both sigma receptors to different degrees. However, only six of them showed higher affinity toward sigma R-1 than sigma R-2 with the highest binding preference to sigma R-1 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/sigma(1) receptor activity as can be seen by comparing the data for compounds 4 and 5 (hH(3)R = 3.17 and 7.70 nM, sigma R-1 K = 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 sigma(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 sigma(l) 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.

Automated summary

Recent studies have shown that some clinically evaluated histamine H-3 receptor antagonists have nanomolar affinity at sigma-1 receptors. Among 20 representative structures of H3R ligands tested, six showed higher affinity towards sigma R-1 than sigma R-2, with the piperidine moiety being a critical structural element for dual H-3/sigma(1) receptor activity. Molecular modeling techniques identified high-affinity lead structures for further evaluation, showing promising antinociceptive activity in vivo and potential as dual-acting compounds for improving pain therapies.