The evolution of histamine H₃ antagonists/inverse agonists

Curr Top Med Chem. 2011;11(6):648-60. doi: 10.2174/1568026611109060648.


This article describes our efforts along with recent advances in the development, biological evaluation and clinical proof of concept of small molecule histamine H₃ antagonists/inverse agonists. The H3 receptor is a presynaptic autoreceptor within the Class A GPCR family, but also functions as a heteroreceptor modulating levels of neurotransmitters such as dopamine, acetylcholine, norepinephrine, serotonin, GABA and glutamate. Thus, H₃R has garnered a great deal of interest from the pharmaceutical industry for the possible treatment of obesity, epilepsy, sleep/wake, schizophrenia, Alzheimer's disease, neuropathic pain and ADHD. Within the two main classes of H₃ ligands, both imidazole and non-imidazole derived, have shown sufficient potency and specificity which culminated with efficacy in preclinical models for various CNS disorders. Importantly, conserved elements have been identified within the small molecule H₃ ligand scaffolds that resulted in a highly predictive pharmacophore model. Understanding of the pharmacophore model has allowed several groups to dial H₃R activity into scaffolds designed for other CNS targets, and engender directed polypharmacology. Moreover, Abbott, GSK, Pfizer and several others have reported positive Phase I and/or Phase II data with structurally diverse H₃R antagonists/inverse agonists.

Publication types

  • Review

MeSH terms

  • Animals
  • Central Nervous System Diseases / drug therapy
  • Central Nervous System Diseases / metabolism
  • Drug Discovery
  • Drug Inverse Agonism*
  • Histamine Agonists / chemical synthesis
  • Histamine Agonists / chemistry
  • Histamine Agonists / pharmacology*
  • Histamine H3 Antagonists / chemical synthesis
  • Histamine H3 Antagonists / chemistry
  • Histamine H3 Antagonists / pharmacology*
  • Humans
  • Ligands
  • Receptors, Histamine H3 / metabolism
  • Structure-Activity Relationship


  • Histamine Agonists
  • Histamine H3 Antagonists
  • Ligands
  • Receptors, Histamine H3