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

In an attempt to extend recent studies showing that some clinically evaluated histamine H receptor (H R) antagonists possess nanomolar affinity at sigma-1 receptors (σ R), we selected 20 representative structures among our previously reported H 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 R than σ R with the highest binding preference to σ R for compounds , , and . 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 /σ receptor activity as can be seen by comparing the data for compounds and (hH R = 3.17 and 7.70 nM, σ R = 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 and as lead structures for further evaluation. Interestingly, both ligands turned out to be high-affinity histamine H and σ receptor antagonists with negligible affinity at the other histamine receptor subtypes and promising antinociceptive activity . Considering that many literature data clearly indicate high preclinical efficacy of individual selective σ or H 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.