The evolution of histamine H₃ antagonists/inverse agonists.

Lebois EP, Jones CK, Lindsley CW
Curr Top Med Chem. 2011 11 (6): 648-60

PMID: 21261594 · 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.

MeSH Terms (10)

Animals Central Nervous System Diseases Drug Discovery Drug Inverse Agonism Histamine Agonists Histamine H3 Antagonists Humans Ligands Receptors, Histamine H3 Structure-Activity Relationship

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