Potential utility of histamine H3 receptor antagonist pharmacophore in antipsychotics

Bioorg Med Chem Lett. 2009 Jan 15;19(2):538-42. doi: 10.1016/j.bmcl.2008.09.012. Epub 2008 Sep 7.


Histamine H3 receptor (H3R) antagonists have some antipsychotic properties although the clear molecular mechanism is still unknown. As actually the most effective and less side effective antipsychotics are drugs with multiple targets we have designed typical and atypical neuroleptics with an additional histamine H3 pharmacophore. The 4-(3-piperidinopropoxy)phenyl pharmacophore moiety has been linked to amitriptyline, maprotiline, chlorpromazine, chlorprothixene, fluphenazine, and clozapine. Amide, amine and ester elements have been used generally to maintain or slightly shift affinity at dopamine D(2)-like receptors (D2 and D3), to decrease affinity at histamine H(1) receptors, and to obtain H3R ligands with low nanomolar or subnanomolar affinity. Change of effects at D(1)-like receptors (D1) and (D5) were heterogeneous. With these newly profiled compounds different antipsychotic properties might be achieved.

MeSH terms

  • Animals
  • Antipsychotic Agents / pharmacology*
  • CHO Cells
  • Cell Line
  • Cricetinae
  • Cricetulus
  • Histamine Antagonists / pharmacology*
  • Humans
  • Radioligand Assay
  • Receptors, Histamine H3 / drug effects*


  • Antipsychotic Agents
  • Histamine Antagonists
  • Receptors, Histamine H3