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

Abstract

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 <b>5</b>, <b>11</b>, and <b>12</b>. 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 <b>4</b> and <b>5</b> (hH₃R <i>K</i>_i = 3.17 and 7.70 nM, σ₁R <i>K</i>_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 <b>5</b> and <b>11</b> 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 <i>in vivo</i>. 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.