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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 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 H₃/σ₁ receptor activity as can be seen by comparing the data for compounds 4 and 5 (hH₃R K_i = 3.17 and 7.70 nM, σ₁R K_i = 1531 and 3.64 nM, respectively), where piperidine is replaced by piperazine. We identified the …