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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.