Development of a New Class of Nonimidazole Histamine H(3) Receptor Ligands With Combined Inhibitory Histamine N-methyltransferase Activity

J Med Chem. 2002 Feb 28;45(5):1128-41. doi: 10.1021/jm0110845.


In search of novel ways to enhance histaminergic neurotransmission in the central nervous system, a new class of nonimidazole histamine H(3) receptor ligands were developed that simultaneously possess strong inhibitory activity on the main histamine metabolizing enzyme, histamine N-methyltransferase (HMT). The novel compounds contain an aminoquinoline moiety, which is an important structural feature for HMT inhibitory activity, connected by different spacers to a piperidino group (for H(3) receptor antagonism). Variation of the spacer structure provides two different series of compounds. One series, having only an alkylene spacer between the basic centers, led to highly potent HMT inhibitors with moderate to high affinity at human histamine H(3) receptors. The second series possesses a p-phenoxypropyl spacer, which may be extended by another alkylene chain. This latter series also showed strong inhibitory activity on HMT, and in most cases, the H(3) receptor affinity even surpassed that of the first series. One of the most potent compounds with this dual mode of action is 4-(4-(3-piperidinopropoxy)phenylamino)quinoline (34) (hH(3), K(i) = 0.09 nM; HMT, IC(50) = 51 nM). This class of compounds showed high antagonist potency and good H(3) receptor selectivity in functional assays in guinea pig on H(1), H(2), and H(3) receptors. Because of low or missing in vivo activity of two selected compounds, the proof of concept of these valuable pharmacological tools for the supposed superior overall enhancing effect on histaminergic neurotransmission failed to appear hitherto.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / drug effects
  • Brain / metabolism
  • CHO Cells
  • Cricetinae
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Guinea Pigs
  • Histamine / metabolism
  • Histamine Antagonists / chemical synthesis*
  • Histamine Antagonists / chemistry
  • Histamine Antagonists / pharmacology
  • Histamine N-Methyltransferase / antagonists & inhibitors*
  • Humans
  • Ileum / drug effects
  • Ileum / physiology
  • In Vitro Techniques
  • Ligands
  • Mice
  • Muscle, Smooth / drug effects
  • Muscle, Smooth / physiology
  • Piperidines / chemical synthesis*
  • Piperidines / chemistry
  • Piperidines / pharmacology
  • Quinolines / chemical synthesis*
  • Quinolines / chemistry
  • Quinolines / pharmacology
  • Radioligand Assay
  • Rats
  • Receptors, Histamine H3 / drug effects*
  • Structure-Activity Relationship


  • 4-(4-(3-piperidinopropoxy)phenylamino)quinoline
  • Enzyme Inhibitors
  • Histamine Antagonists
  • Ligands
  • Piperidines
  • Quinolines
  • Receptors, Histamine H3
  • Histamine
  • Histamine N-Methyltransferase